Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV

Can HIV Be Cured and Should We Try?

CROI OVERVIEW The 13th Conference on Retroviruses and Opportunistic Infections (CROI) was held in Denver, Colorado, on February 5-8, 2006. This conference served as a backdrop for reflecting on the 25th anniversary of acquired immunodeficiency syndrome ([AIDS] first described in June 1981) and the 10th anniversary of highly active antiretroviral therapy ([HAART] first widely available in 1996). This year, approximately 4000 leading researchers and clinicians from 85 countries (54% from North America) were able to attend 6 plenary lectures, 7 roundtable symposia, 5 thematic research overviews, 122 original oral abstract presentations, 734 poster presentations, 9 poster discussions, and late breakers. In this month's Snapshots, we review some highlights of the conference. Abstracts, webcasts, and podcasts are accessible through the conference website (www.retroconference.org/2006). TEN YEARS OF HAART John G. Bartlett from Johns Hopkins University gave a plenary lecture covering the most important advances in the therapy of human immunodeficiency virus (HIV) infection over the past decade. He outlined the method of doing HIV clinical trials (including the Food and Drug Administration's approval of HIV RNA as the first laboratory marker accepted as an end point for any infectious disease) and a series of clinical trials which have led to current guidelines. He concluded by looking forward to the soon to be completed head-to-head study of efavirenz and lopinavir/ritonavir (ACTG 5142), the marketing of the first once daily coformulation of tenofovir/emtricitabine/efavirenz (the single HAART pill), the availability of new salvage agents (the TMC114 Expanded Access Program and others in the near future), the potential for multidrug induction followed by single boosted protease inhibitor (PI) maintenance (lopinavir/ritonavir and atazanavir/ritonavir), and the continued development of new antiretroviral classes (to be discussed later). DIAGNOSIS AND TRANSMISSION Since 2002, North Carolina's Screening & Tracing Active Transmission (STAT) program has used a combined HIV antibody and RNA testing algorithm to identify cases of primary HIV in the antibody "window" period. Patterson et al (abstract 370) demonstrated that the standard antibody test missed 4% of the pregnant women in North Carolina who are infected with HIV. They were able to prevent vertical transmission despite high viremia in the mother by initiating antiretroviral therapy. Following reports from New York City and San Francisco, that there might be excessive false-positive oral fluid rapid HIV tests (OraQuick Advance HIV1/2 Rapid Antibody Test approved in March 2004), the Centers for Disease Control and Prevention (CDC) initiated an investigation (abstract 34LBb) that confirmed the reliability of the test and identified site-specific factors associated with high false-positives. The CDC is in the process of revising recommendations for HIV testing with a goal of increasing the proportion of HIV-infected Americans who know their infection status (abstract 164). One proposal is for a voluntary "opt-out" consent procedure for HIV testing as part of the consent for general care and expanded rescreening in the third trimester for women found to be HIV-negative early in pregnancy. The CDC also presented data (abstract 27) on trends in HIV/AIDS among non-Hispanic blacks (NHBs) in the United States. Between 2001 and 2004, 156,000 newly diagnosed cases of HIV infection were reported in 33 states; NHBs accounted for 51% of cases (although they constitute only 13% of the US population). Among NHBs, trends in transmission remained stable or declined in all categories analyzed except in men who have sex with men (MSM). The National Cancer Institute (abstract 26) reported that the presence of HLA-B Bw4 alleles was associated with a decreased risk of HIV transmission from infected hemophiliac men to their female sex partners and speculated that there might be a decreased seminal HIV RNA load in this setting. A multicenter adolescent trials network study (ATN029, abstract 21) provided evidence for transmitted resistance (genotypic in 18% and phenotypic in 22%) among recently infected youth aged 16 to 24 years. These data are very disturbing and represent the highest prevalence of primary HIV resistance in the United States. Thomas Quinn (abstract 120) gave an entertaining plenary lecture entitled "Circumcision and HIV Transmission: The Cutting Edge." He reviewed the evidence supporting male circumcision for the prevention of HIV transmission, including epidemiology (countries with high rates of circumcision have low HIV rates and vice versa), cohort studies (demonstrating a 44%-80% reduction in transmission), biologic mechanisms (9-fold fewer HIV targets in stratified epithelium vs. mucosal inner foreskin), and clinical trials (3 prospective clinical trials in Africa). A group from the University of Washington in Seattle (abstract 163) reported that "serosorting" (the practice in which people who know their HIV status search for partners of the same status) is common and can lead either to decreased HIV transmission (as has been seen among MSM in San Francisco) or to superinfection, a generally rare event but the topic of several abstracts (91, 92, 293). A European group (abstract 33LB) demonstrated in the first randomized controlled trial that active herpes simplex virus type 2 (HSV-2) infection is causally related to increased HIV genital shedding and that HSV-2 suppression with valacyclovir decreased genital HIV RNA by 25% and plasma HIV RNA by 40%. This obviously could have an impact on HIV transmission. CURRENT ANTIRETROVIRAL THERAPY Several posters (525, 529, 530, 769) offered new insights into the timing of initiating HAART, each favoring treating patients earlier (ie, at a higher CD4 lymphocyte count nadir); the HIV Outpatient Study even demonstrated decreased long-term toxicity (peripheral neuropathy, lipoatrophy, and renal insufficiency) if this strategy is used. Another multinational study (abstract 351) supported earlier use of antiretrovirals to decrease the risk of HIV encephalopathy. Several studies looked at compartmentalization of antiretroviral agents. Oral abstract 74 showed the best central nervous system penetration among nucleoside reverse transcriptase inhibitors ([NRTIs] zidovudine and abacavir), non-NRTIs ([NNRTIs] nevirapine), and PI (all boosted including fosamprenavir, lopinavir, atazanavir, and indinavir but not saquinavir). Oral abstract 129 explored genital tract pharmacokinetics of antiretrovirals and potential implications for preexposure and postexposure prophylaxis. In addition to previous studies on tenofovir, agents with the greatest ratio of genital tract-to-plasma drug levels included emtricitabine, zidovudine, and lamivudine followed by atazanavir and didanosine. Structured treatment interruptions have been the subject of numerous studies in various cohorts (eg, primary HIV infection and those seeking a "drug holiday"). At this conference, both time-based and CD4-guided treatment interruption studies were presented. The results of these studies (abstracts 102, 103, 104, 105LB, and 106LB) provided some mixed messages, but certain strategies were definitely associated with poor outcomes. The most important data came from the Strategies for Management of Anti-Retroviral Therapy (SMART) study presented by Wafaa El-Sadr. Patients in this huge study (N = 5472) were randomized to a continuous HAART arm (viral suppression [VS]) or to a discontinuation arm (the drug-conservation group [DC], stopping when the CD4 >350 and resuming when the CD4 <250). On January 10, 2006, the Drug Safety and Monitoring Board recommended stopping further enrollment because of a significantly increased risk of disease progression (AIDS or death) in the DC arm. Another trial from West Africa (ANRS 1269 Trivacan Trial) using the same CD4 targets as SMART demonstrated a 2-fold higher rate of serious morbidity (mainly invasive bacterial diseases) in the discontinuation/resumption arm. In contrast, the multinational STACCATO trial (using a CD4 of 350 to stop and resume therapy) showed similar rates of treatment failure and complications in both arms. Although a great deal of further analysis is needed, it would be prudent to resume HAART at the higher CD4 level of 350 if CD4-based treatment interruption is used. Time-based interruptions (eg, the ongoing FOTO study using 5 days on/2 days off) seek to decrease exposure to antiretrovirals, adverse effects, and overall cost. The Window-ANRS 106 trial demonstrated that a fixed structured interruption of 8 weeks off/8 weeks on appeared clinically and immunologically safe over 96 weeks while sparing 48.5% of drug exposure. The 48-week data reported on the use of tipranavir/ritonavir in antiretroviral therapy-experienced patients (combined data from RESIST 1 and 2 studies [abstract 520]). Treatment response (≥1 log reduction in HIV RNA) with tipranavir/ritonavir was achieved at approximately twice the rate of comparator PI/ritonavir. The rate of virological suppression to a viral load of less than 50 copies/mL occurred in 22.8% and 10.2% of tipranavir/ritonavir- and comparator PI/ritonavir-treated patients, respectively. Responses to tipranavir/ritonavir were greater in patients with a lower baseline viral load or higher baseline CD4 count. The 48-week data were also presented comparing atazanavir with or without ritonavir in antiretroviral-naive patients (abstract 107LB). Virological response rates were similar in the 2 groups; 75% and 70% achieved an HIV RNA of less than 50 copies/mL in the boosted and unboosted groups, respectively. However, virological failure because of viral rebound was greater in the unboosted group. Furthermore, whereas no PI mutations were identified in the boosted group, 3 patients in the unboosted group developed the I50L mutation. Adverse events were more common in the boosted group, leading to more discontinuations (8% vs. 1%). Specifically, jaundice occurred in 22% of patients in the boosted group compared with 7% in the unboosted group. A growing area of research involves simplifying the therapy with only a boosted PI. One such study presented at CROI assessed simplification to ritonavir-boosted atazanavir in 34 patients. Patients enrolled were receiving their first PI plus 2 NRTIs and had documented virological suppression for at least 48 weeks. Thirty-one patients maintained virological suppression at 24 weeks after simplification. Of the 3 patients who experienced virological failure, 2 patients had undetectable atazanavir concentrations. No PI mutations were detected upon genotyping studies. FUTURE ANTIRETROVIRAL THERAPY Twenty-one antiretroviral agents are currently marketed in the United States; only 1, enfuvirtide, acts extracellularly. New names have emerged for some of the second-generation compounds of the NRTI (dexelvucitabine [D-d4FC]), NNRTI (etravirine [TMC125]), and PI (darunavir [TMC114] and brecanavir [GW640385]) classes. Numerous agents from novel classes were discussed, including entry inhibitors, integrase inhibitors, and maturation inhibitors. Two new entry inhibitors (TRI-1144 and TRI-999) show activity against enfuvirtide-resistant HIV, and pharmacokinetic data suggest once weekly dosing is feasible. Research is ongoing with co-receptor inhibitors. Vicriviroc, a CCR5 co-receptor antagonist, was studied with zidovudine/lamivudine in a phase 2 study (abstract 161LB). The Data Safety Monitoring Board terminated the study prematurely because of virological breakthrough. Such data suggest that more research is necessary to define the role of co-receptor inhibitors. The orally bioavailable CXCR4 co-receptor inhibitors KRH-3955 and KRH-3140 were introduced and showed promising results in animal studies (abstract 49LB). Clinical trial data were presented for 2 integrase inhibitors in development (abstracts 159LB and 160LB). Both MK-0518 and GS-9137 (JTK-303), along with an optimized background regimen, exhibited substantial antiviral activity. MK-0518 was studied at 3 doses in patients with HIV resistant to all 3 classes of oral antiretrovirals. At week 8, approximately two thirds of patients had HIV RNA of less than 50 copies/mL. PA-457 is a first-in-class maturation inhibitor that was studied as monotherapy in HIV-positive patients (abstract 52). Although the primary goal of the study was to determine pharmacokinetics, there was a 1.1 log reduction in the HIV RNA after 10 days of treatment at the highest dose, and no resistance to PA-457 was detected. An in vitro study showed that PA-457 has wild-type activity against drug-resistant HIV-1 isolates, and synergy was demonstrated with currently approved antiretroviral classes (abstract 509). Data were presented on 2 novel NRTIs in development. GS9148 is an adenosine analogue similar to tenofovir (abstract 45). In vitro assays showed minimal potential for metabolic toxicity. GS9148 was active against HIV with multiple NRTI mutations, including strains with up to 5 thymidine analogue mutations (TAMs). The Q151M resistance complex was the only mutation that significantly affected GS9148. The peripheral blood mononuclear cell half-life was greater than 24 hours in an animal model, suggesting that once daily dosing is possible. The second novel NRTI presented is 1-(β-D-dioxolane)thymine, a thymidine kinase-dependent NRTI (abstract 46). It also has considerable activity against NRTI-resistant HIV. The presence of TAMs and/or the M184V mutation did not affect susceptibility. However, the 69 insertion mutation and the Q151M complex produced 1-(β-D-dioxolane)thymine resistance. Another new class of antiretrovirals is the nucleotide-competing reverse transcriptase inhibitors, which form a dead-end complex with reverse transcriptase after pyrimidine incorporation (abstract 47). The class representative nucleotide-competing reverse transcriptase inhibitor type 1 displayed antiviral activity, but resistance was seen with the M184V mutation, whereas the K65R mutation caused hypersusceptibility. Lastly, a PI in development called SPI-256 demonstrated greater in vitro potency than currently approved PIs and was similarly active against wild-type and multidrug-resistant HIV-1 isolates (abstract 501). DRUG-DRUG INTERACTIONS Among the drug interaction studies at CROI, there was a focus on potential dual-PI therapies and on an investigational NNRTI called TMC125 currently in phase 3 clinical trials. In the first of 3 studies with TMC125, no significant interaction was detected when TMC125 was administered with the investigational PI TMC114/ritonavir (abstract 575c). In a similar study, no significant interaction was found between TMC125 and either saquinavir or lopinavir/ritonavir (abstract 575b). However, when administered with tipranavir 500 mg and ritonavir 200 mg, TMC125 concentrations were reduced to less than 30% of those with TMC125 alone (abstract 583). Investigators recommend avoiding this antiretroviral combination. Previous studies have also shown that tipranavir significantly reduces lopinavir concentrations when administered with lopinavir/ritonavir. This interaction was studied in patients given 1 of 2 investigational dosing regimens (abstract 584). All patients received standard twice daily dosing of lopinavir/ritonavir. One group also received 500 mg tipranavir plus 200 mg ritonavir, both BID, whereas another group received 500 mg tipranavir plus 133 mg lopinavir/33 mg ritonavir plus 100 mg ritonavir, all BID. In both groups, median trough concentrations of lopinavir were comparable with standard dosing of lopinavir/ritonavir; however, there was significant interpatient variability. The authors recommend therapeutic drug monitoring if one of these regimens is prescribed. In another dual-PI study, concentrations of saquinavir were measured when given with either ritonavir or atazanavir (abstract 586). The regimen of 1500 mg saquinavir plus 200 mg atazanavir, both BID, resulted in potentially therapeutic concentrations of both PI. However, the boosting effect of atazanavir was not as strong as ritonavir (saquinavir Cmin 599 ng/mL vs. 129 ng/mL). A third dual-PI study found favorable concentrations when 300 mg/day atazanavir is combined with standard dosing lopinavir/ritonavir (abstract 585). Finally, a study of once daily 1400 mg fosamprenavir plus 400 mg atazanavir found a 2-way interaction that resulted in a 57% reduction in the Cmin of atazanavir but a 283% increase in the Cmin of amprenavir (abstract 587). The authors of this study were unable to speculate on the clinical utility of this combination. PHARMACOKINETICS OF PROTEASE INHIBITORS IN PREGNANCY The US Food and Drug Administration recently issued warnings of lopinavir concentrations in women lopinavir/ritonavir the third trimester of pregnancy. Two studies were presented at CROI that this concentrations were measured in a cohort of 16 women in the third trimester of (abstract All patients received 3 of lopinavir/ritonavir twice trough concentrations were detected in and of had an undetectable HIV was in the 2 with a viral In a similar study, a higher of lopinavir/ritonavir was studied the third twice daily (abstract Of the women with available lopinavir concentrations were achieved at the higher however, excessive concentrations were achieved with the higher at 2 weeks Another group of measured trough concentrations in pregnant patients receiving a of mg or mg (abstract Patients in this study were not in the third trimester of pregnancy. of patients had a trough the of 1 The was increased to 1500 mg in 8 patients, but only 6 achieved the The data presented in these studies further the utility of therapeutic drug monitoring pregnancy. Two novel nucleoside analogue mutations were described at this In the mutation was among of patients receiving the NRTI of tenofovir, and The mutation is also by and the investigational NRTI which is an adenosine analogue similar to tenofovir Investigators found that the mutation resistance by (abstract However, to thymidine in the presence of suggesting that this mutation is to the development of similar to is seen with the K65R mutation. The mutation is another novel reverse transcriptase (abstract This mutation a increase in resistance to zidovudine and but at a of reduced to study the of mutations, such as of TAMs greater resistance to than lamivudine (abstract Of isolates with 3 to TAMs and no M184V mutation, were resistant to emtricitabine, whereas only were resistant to Another study confirmed that the presence of both and to efavirenz (abstract was significantly reduced with on an analysis of the this mutation was found to in with in is with both Two studies documented the of thymidine if resistance is associated with the K65R mutation. Among 3 patients virological failure associated with the K65R mutation, zidovudine resulted in viral load to less than 50 the strains were resistant to all the in the regimen (abstract A similar analysis of isolates with the K65R mutations found that of a thymidine analogue in the salvage regimen a virological response (abstract No CROI would be without a of resistance associated with investigational antiretroviral agents. The investigational NNRTI TMC125 was found to activity against HIV with baseline NNRTI however, the viral load reduction was significantly less in the presence of 3 or more baseline NNRTI mutations and HIV RNA with 1 and mutations, (abstract associated with the investigational PI TMC114/ritonavir was also An analysis of 2 studies of TMC114/ritonavir in patients 1 and was The analysis certain mutations associated with reduced response to TMC114/ritonavir (abstract The presence of or at baseline was associated with a lower decrease in viral Virological rebound was associated with the development of mutations or OF THERAPY AND each conference, we more metabolic and complications of long-term antiretroviral all from studies in developed Although has been in the United because of as compared with it a in the in fixed A study from (abstract looking at the use of and widely available as another from The Data on Adverse of study demonstrated that increased PI exposure was associated with an increased risk of by However, both the SMART and HIV Outpatient Study data found that increased disease risk was associated with risk factors of disease risk was reduced by and agents. The ongoing Study concluded that the metabolic syndrome as of the and blood or is more common in than men The CDC data from patients and reported on the of in HIV which were significantly higher in HIV infection and their risk when compared with a included the 3 and and 7 disease and was no increased risk of or renal and a decreased risk of and is the of HIV-infected patients and can be more and more in this setting. researchers used in HIV-infected patients with and found that they were able to early in 75% of the test was and The in with viral was a prospective study the role of in virus in the HAART for HAART, was associated with a decrease in the risk of transmission of risk (abstract In a study of patients, ratio was used to significant ratio were found in of patients with HIV infection of patients with 22% of patients with virus and of patients with risk factors associated with significant were CD4 and HAART (abstract A study of patients with of infection by undetectable viral showed that patients are at risk for of Of patients of viral occurred in 6 of HIV-infected patients but in of 16 HIV-negative patients for a median of viral load testing be for patients with of infection (abstract Two studies demonstrated that high risk and mucosal factors are associated with transmission of infection in factors included and including with and activity the of (abstracts and A CD4 cell response in patients with has been of patients demonstrated no significant in CD4 response in patients after of viral suppression in compared with HIV However, the study found that with 2 or 3 had a CD4 response compared with 1 or (abstract In an study of 24 patients 1, or plus to therapy for 48 weeks was compared with dosing with induction of for the first for the and for weeks. No significant in virological response was seen with vs. in the induction arm = treatment resulted in a reduction in in one third of patients in the induction arm compared with in the treatment group (abstract A study to the of alone compared with plus was in all patients were with monotherapy for weeks. Patients with undetectable RNA at weeks continued treatment with monotherapy to 48 whereas those with RNA were with therapy with the addition of The rate in patients who received monotherapy for 48 weeks was compared with in patients who did not viral suppression at weeks. The study the of viral load with to treatment outcomes. This strategy be in patients with or a for use (abstract An analysis of the trial data demonstrated similar in patients with 1 of baseline RNA 13% achieved rapid virological response and had an (abstract A study looking at the impact of the of treatment for patients to weeks in patients who achieved undetectable RNA levels at 24 weeks did not show any significant in between the 2 rate in the 48-week treatment group vs. in the group = (abstract a study showed a significant decrease in after treatment in patients who achieved (abstract In patients, CD4 were not of response to Patients who have had have similar response rates compared with patients with high baseline CD4 (abstract was found to be higher in patients vs. in HIV were most associated with HIV of patients of disease (abstract In a study, patients were found to have similar infection rates compared with patients receiving The count did not with infection rates (abstract A study demonstrated more in patients compared with patients. The was not caused by drug use and be from infection (abstract of viral response at week of treatment was in 2 and 3 patients with or in with response rates were for and for of treatment virological and rate were and in patients who achieved RNA levels less than 100 after weeks compared with and in patients with RNA levels greater than 100 at weeks to be a to of treatment (abstract is a strong of Among patients the of patients with was greatest with NNRTI greater than PI greater than boosted PI greater than NRTI (abstract In contrast, a study of patients to determine the risk of in patients concluded that patients on HAART were not at increased risk of compared with patients of HAART risk vs. = drug patients to be at higher risk for (abstract New therapies for are very for the and are inhibitors of the These have demonstrated rapid and in viral but resistance is a In a study of a log was achieved at In a study of with plus of patients with 1 had undetectable levels at mutations associated with resistance and level resistance and or high level resistance of of PIs be used in therapy with and inhibitors are nucleoside and viral inhibitors. to inhibitors also for resistance mutations and and be used in with agents (abstracts and Lastly, there were several plus lamivudine was to tenofovir or alone for the treatment of patients at 24 weeks (abstract was also for treatment of infection in significant in and no virological (abstract infection with was seen in to of patients. would that all HIV-infected patients be for infection given the implications for the of infection was not greater in patients compared with patients (abstracts and A study the of demonstrated that occurred in 34 cases in patients compared with cases in patients against factors for failure after for and CD4 count were not receiving HAART and (abstract A review such as this to the that CROI such a each the to website for further and

Addressing HIV-1 latency with Flow-FISH: Finding, characterizing and targeting HIV-1 infected cells.

Approximately 30 years ago, in June 1981, it was reported from theCenter forDiseaseControl andPrevention (CDC) that five, otherwise healthy, homosexual men in California had presented with pneumonia caused by Pneumocystis jiroveci pneumonia, a rare disease seen exclusively in individualswith a severely suppressed immune system. Several reports confirmed the initial observation and lent support to the possibility that a new sexually transmitted, infectious agent was circulating within the gay community in the United States. The clinical condition was named acquired immunodeficiency syndrome (AIDS). Two years later, a research team at the Institut Pasteur under the guidance of Francoise Barre-Sinoussi and Luc Montagnier isolated human immunodeficiency virus (HIV), the causative agent of AIDS, from a lymph node biopsy of a French patient. The isolation and characterization of HIV paved the way for the design of diagnosticmethods to identify the virus in blood andbloodproducts and towards the development of novel antiretroviral treatment (ART) to control HIV replication in infected patients. For their discoveries, Barre-Sinoussi and Montagnier were awarded the Nobel Prize in Physiology and Medicine in 2008.

The relationship of serum human immunodeficiency virus-1 (HIV-1) RNA levels to HIV-1 RNA levels in other compartments, such as the lungs, is not well characterized. The purpose of this study was to determine the viral burden of HIV-1 in the lungs by comparing HIV-1 RNA in cell-free bronchoalveolar lavage fluid (BALF) with that in serum. Specimens were examined from 77 HIV-seropositive adults (CD4(+) cell counts: 0 to 700 cells/mm(3); 48% receiving prescribed antiretroviral agents), comprising 43 asymptomatic individuals who were compared with 34 persons with active lung disease caused by Pneumocystis carinii (n = 26), bacteria (n = 3), Mycobacterium avium complex (n = 2), Nocardia sp. (n = 1), Aspergillus sp. (n = 1), or pulmonary Kaposi's sarcoma (n = 1). For serum HIV-1 RNA, the proportion of subjects with detectable levels and the mean values were similar for asymptomatic individuals and persons with active lung disease (85% versus 86%, respectively) (6.64 x 10(4) versus 1. 81 x 10(5) HIV-1 RNA copies/ml; p = 0.13). In contrast, HIV-1 RNA in BALF was more often detected (16% versus 62%; p = 0.001), and mean values were higher (1.04 x 10(5) versus 3.31 x 10(6) HIV-1 RNA copies/ml; p = 0.032), in subjects with active lung disease than in asymptomatic subjects, independent of early or advanced clinical stages of HIV-related disease. For both study groups, HIV-1 RNA levels in BALF exceeded those in serum in 56% of cases by up to 66-fold, and did not correlate with local levels of tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or interleukin-16. HIV-1 proviral DNA in cells from BALF was detected in up to 86% of subjects, more frequently in persons with advanced HIV disease (p = 0.0496), and often involved > 10% of BALF cells, but did not correlate with HIV-1 RNA detected in BALF. These data provide evidence for active HIV-1 replication in the lungs. HIV-1 replication is compartmentalized relative to serum, may be restricted, is independent of HIV-1 proviral DNA and clinical stage of HIV, and may be influenced by pulmonary disease such as P. carinii pneumonia or by other local or lung-specific factors. The lungs represent a large reservoir for HIV-1, and may present a source of persistent HIV-1 replication even during periods of apparent clinical latency of HIV-1 infection.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review).

The study objective was to identify optimal starting criteria regarding levels of CD4 cells and human immunodeficiency virus (HIV) RNA at initiation of highly active antiretroviral therapy (HAART) in chronically HIV-infected people. All 162 treatment-naive patients in the centre who were treated for at least 180 d with 2 nucleoside reverse transcriptase inhibitors plus at least 1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor were included. The patients were stratified according to their levels of CD4 cells and HIV RNA at initiation of therapy. Baseline CD4 groups were: group 1: CD4 < 0.1 x 10(9)/l; group 2: CD4 > or = 0.1 and < 0.2 x 10(9)/l; group 3: CD4 > or = 0.2 and < 0.35 x 10(9)/l; and group 4: CD4 > or = 0.35 x 10(9)/l. Two patients died and 38 developed an HIV-related disease (Centers for Disease Control category B or C) during the study. The prevalence of HIV-related disease before HAART was significantly increased in groups 1 and 2 compared with groups 3 and 4. The level of HIV RNA was not associated with HIV-related disease either before or after treatment initiation. Subjects in group 1 had an increased risk of HIV-related disease after treatment initiation both in univariate Cox analysis and after adjustment for HIV RNA, gender, mode of transmission and age, compared with group 2 [adjusted risk ratio with 95% confidence interval: 3.76 (1.48-9.61)], group 3 [5.90 (2.07-16.95)] and group 4 [5.05 (1.96-12.90)]. The association between CD4 count and morbidity appeared to be particularly strong for older subjects. In conclusion, this study suggests that in chronically HIV-infected individuals, in most cases HAART can be withheld until the CD4 cell count falls towards 0.2 x 10(9)/l.

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

To define the determinants of anal-rectal shedding of human immunodeficiency virus (HIV) DNA and RNA, 374 HIV-seropositive homosexual men were tested. Factors independently associated with detection of anal-rectal HIV DNA included anal-rectal inflammation and detection of anal human papillomavirus DNA; predictors of HIV RNA included detection of anal-rectal HIV DNA, anal-rectal inflammation, and high plasma HIV RNA levels. The latter (>10,000 copies/mL) was the main determinant of anal-rectal HIV RNA shedding when HIV DNA (e.g., HIV-infected cells) was not detected in the anal-rectal sample. The local presence of HIV-infected cells and local inflammation were the principal determinants of HIV RNA among those with low (<10,000 copies/mL) plasma HIV RNA load. Among those with anal-rectal HIV DNA present, increased HIV RNA plasma load did not increase the risk of shedding of HIV RNA into the anal-rectal canal.

Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine

The objective of this study was to conduct an analysis of peripheral blood Th17 cells with the ability to home to gut mucosa (CD4+ Th17+ β7+ ) during recent or chronic human immunodeficiency virus (HIV) infections. The relationship between HIV load and systemic inflammation markers was studied. Twenty-five patients with recent (n=10) or chronic (n=15) untreated HIV infections; 30 treated HIV-infected patients with undetectable HIV load at the time of inclusion and 30 healthy controls were included. Bacterial translocation markers (16S rDNA), soluble CD14 (sCD14) and interleukin (IL)-6 monocyte activation parameters, CD4/CD8 ratio and T helper type 17 (Th17) subpopulations [CD4+ Th17+ expressing the IL-23 receptor (IL-23R) or β7] were analysed at baseline and after 6 and 12months of anti-retroviral therapy (ART). 16S rDNA was detected in all patients. Significantly increased serum levels of sCD14 and IL-6 and a decreased CD4/CD8 ratio were observed in patients. Similar percentages of CD4+ IL-23R+ and CD4+ Th17+ β7+ cells were observed in healthy controls and patients at baseline. After 12months of therapy, patients with a recent HIV infection showed significant increases of CD4+ IL-23R+ and CD4+ Th17+ β7+ cell percentages and a decrease in IL-6 levels, although 16S rDNA continued to be detectable in all patients. No significant differences were observed in Th17 subpopulations in patients with chronic HIV infection after therapy. Early initiation of ART helps to increase the number of Th17 cells with the ability to home to the intestinal mucosa and to partially restore gut mucosal homeostasis. These results provide a rationale for initiating ART during the acute phase of HIV infection.

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

Background. CD4(+)/CD8(+) T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation predicts early death and blunted CD4+ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence. Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (<6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologic suppression; at-risk HIV-negative persons were controls. We measured CD4(+)/CD8(+) T-cell activation (percent CD38(+)/HLA-DR(+)) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels). Results. In unadjusted analyses, early ART predicted lower on-therapy CD8(+) T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4+ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035). Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.

Identifying risk factors for human immunodeficiency virus (HIV) rebound after treatment interruption is crucial for designing effective remission strategies. Peripheral blood mononuclear cells from participants in the Zurich HIV Primary Infection Cohort (ZPHI, n = 73) and ACTG study A5345 (n = 44) were analyzed before antiretroviral therapy (ART) interruption. We measured cell-associated HIV RNA, total HIV DNA, and proviral diversity (env gene). Immune phenotyping was conducted by flow cytometry. Cox proportional hazards (PH) models and penalized Cox PH models with an adaptive LASSO penalty identified risk factors for time to rebound (HIV RNA >1000 copies/mL). Late ART initiation was associated with higher rebound risk (shorter time to rebound) as compared to early ART. Higher pre-ART HIV RNA in plasma, total HIV DNA, and increased cellular HIV transcription at the time of ART interruption were associated with higher rebound risk. Higher proviral diversity was associated with higher rebound risk but only among male participants and those enrolled in the ZPHI cohort. Fewer CD4+ T cells at ART interruption, higher proportions of effector and terminally differentiated T cells, and more activated and exhausted T cells were associated with higher rebound risk, primarily in early-treated participants. No significant immunological risk factors were found in participants treated during chronic HIV. In the combined cohort, total HIV DNA and terminally differentiated CD8+ T cells appeared to be the most relevant risk factors for time to rebound, as indicated by variable selection in multivariable analysis. These findings underscore the importance of early ART initiation and suggest that tailored interventions based on virologic, immunologic, and demographic factors may help achieve sustained viral suppression. Clinical Trials Registration. NCT00537966 and NCT03001128.

Immune control of human immunodeficiency virus (HIV) is not restored by highly active antiretroviral therapies (HAART) during chronic infection. We examined the capacity of repeated structured therapeutic interruptions (STI) to restore HIV-specific CD4 and CD8 T-cell responses that controlled virus production. Eleven STI (median duration, 7 days; ranges, 4 to 24 days) were performed in three chronically HIV-infected patients with CD4 counts above 400/mm(3) and less than 200 HIV RNA copies/ml after 18 to 21 months of HAART; treatment resumed after 1 week or when virus became detectable. HIV-specific T-cell responses were analyzed by proliferation, gamma interferon (IFN-gamma) production, and enzyme-linked immunospot assays. Seven virus rebounds were observed (median, 4,712 HIV-1 RNA copies/ml) with a median of 7 days during which CD4 and CD8 counts did not significantly change. After treatment resumed, the viral load returned below 200 copies/ml within 3 weeks. Significant CD4 T-cell proliferation and IFN-gamma production against HIV p24 appeared simultaneously with or even before the virus rebounds in all patients. These CD4 responses lasted for less than 3 weeks and disappeared before therapeutic control of the virus had occurred. Increases in the numbers of HIV-specific CD8 T cells were delayed compared to changes in HIV-specific CD4 T-cell responses. No delay or increase in virus doubling time was observed after repeated STI. Iterative reexposure to HIV during short STI in chronically infected patients only transiently mobilized HIV-specific CD4 T1-helper cells, which might be rapidly altered by virus replication. Such kinetics might explain the failure at delaying subsequent virus rebounds and raises concerns about strategies based on STI to restore durable HIV-specific T-cell responses in chronic HIV infection.