Suppression Of Plasma Viremia Research Articles

Genotypic Resistance Testing of HIV-1 DNA in Peripheral Blood Mononuclear Cells.

HIV-1 DNA exists in nonintegrated linear and circular episomal forms and as integrated proviruses. In patients with plasma viremia, most peripheral blood mononuclear cell (PBMC) HIV-1 DNA consists of recently produced nonintegrated virus DNA while in patients with prolonged virological suppression (VS) on antiretroviral therapy (ART), most PBMC HIV-1 DNA consists of proviral DNA produced months to years earlier. Drug-resistance mutations (DRMs) in PBMCs are more likely to coexist with ancestral wild-type virus populations than they are in plasma, explaining why next-generation sequencing is particularly useful for the detection of PBMC-associated DRMs. In patients with ongoing high levels of active virus replication, the DRMs detected in PBMCs and in plasma are usually highly concordant. However, in patients with lower levels of virus replication, it may take several months for plasma virus DRMs to reach detectable levels in PBMCs. This time lag explains why, in patients with VS, PBMC genotypic resistance testing (GRT) is less sensitive than historical plasma virus GRT, if previous episodes of virological failure and emergent DRMs were either not prolonged or not associated with high levels of plasma viremia. Despite the increasing use of PBMC GRT in patients with VS, few studies have examined the predictive value of DRMs on the response to a simplified ART regimen. In this review, we summarize what is known about PBMC HIV-1 DNA dynamics, particularly in patients with suppressed plasma viremia, the methods used for PBMC HIV-1 GRT, and the scenarios in which PBMC GRT has been used clinically.

Killer immunoglobulin-like receptor (KIR) genes are associated with the risk of episodes of high-level and detectable viremia among HIV controllers

Background: HIV controllers (HICs) constitute a heterogeneous group of HIV-1 individuals able to suppress plasma viremia to low or undetectable levels in the absence of antiretroviral therapy. Host genetic factors may be involved in the sustained control of viral replication observed. We investigated the distribution and the potential impact of human leukocyte antigens (HLA)-B and -C alleles, killer immunoglobulin-like receptor (KIR) genes, single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8 and IL-1β inflammasome genes, and CCR5Δ32 mutation on the viral control among HICs. Methods: In total, 28 HICs were categorized as persistent elite controllers (PECs, n = 7), ebbing elite controllers (EECs, n = 7), and viremic controllers (VCs, n = 14) according to the level of natural suppression of viremia. HLA alleles were assigned by sequencing-based typing, KIR alleles by polymerase chain reaction (PCR) sequence-specific amplification, SNPs by real-time PCR, and the CCR5Δ32 mutation by PCR. Results: Significant differences were observed in the pairwise comparisons of protective HLA-B alleles, KIR Bx genotype, KIR2DL3 + C1 pair, KIR2DL5, and KIR2DS5 allelic carrier frequencies among the HIC groups. Multivariate models showed that HICs without the KIR2DL3 allele or without KIR2DL3 + C1/C2 pair, with the HLA-C*08 allele or with the NLRP3 rs10754558-G SNP had a higher mean hazard of a viral load above 2,000 copies/mL, while a lower mean hazard of this event was observed for HICs with KIR2DL5, KIR2DS1, KIR2DS5, and KIR3DS1 alleles. Moreover, HICs with the KIR2DS5 allele had less risk of undergoing viral load (VL) blips within the same normalized period than those participants without this allele, while HICs without the KIR2DL3 allele had a mean higher risk of experiencing VL blips. Conclusions: These results indicate that innate immune mechanisms may play an essential role in modulating the sustained control of viral replication in HICs.

Hepatic Steatosis and Ectopic Fat Are Associated With Differences in Subcutaneous Adipose Tissue Gene Expression in People With HIV.

Persons with human immunodeficiency virus (PWH) have subcutaneous adipose tissue (SAT) dysfunction related to antiretroviral therapy and direct viral effects, which may contribute to a higher risk of nonalcoholic fatty liver disease compared with human immunodeficiency virus–negative individuals. We assessed relationships between SAT expression of major adipocyte regulatory and lipid storage genes with hepatic and other ectopic lipid deposits in PWH. We enrolled 97 PWH on long‐term antiretroviral therapy with suppressed plasma viremia and performed computed tomography measurements of liver attenuation, a measure of hepatic steatosis, skeletal muscle (SM) attenuation, and the volume of abdominal subcutaneous, visceral, and pericardial adipose tissue. Whole SAT gene expression was measured using the Nanostring platform, and relationships with computed tomography imaging and fasting lipids were assessed using multivariable linear regression and network mapping. The cohort had a mean age of 47 years, body mass index of 33.4 kg/m2, and CD4 count of 492 cells/mm3. Lower liver attenuation, a marker of greater steatosis, was associated with differences in SAT gene expression, including lower lipoprotein lipase and acyl‐CoA dehydrogenase, and higher phospholipid transfer protein. Lower liver attenuation clustered with lower visceral adipose tissue (VAT) attenuation and greater VAT volume, pericardial fat volume and triglycerides, but no relationship was observed between liver attenuation and SAT volume, SM attenuation, or low‐density lipoprotein. Conclusion: Liver attenuation was associated with altered SAT expression of genes regulating lipid metabolism and storage, suggesting that SAT dysfunction may contribute to nonalcoholic fatty liver disease in PWH. SAT gene‐expression relationships were similar for VAT volume and attenuation, but not SM, indicating that ectopic lipid deposition may involve multiple pathways.

Extremely low viral reservoir in treated chronically HIV-1-infected individuals.

BackgroundSmall viral reservoirs are found predominantly in HIV-1 controllers and individuals treated during acute/early HIV-1 infection. However, other HIV+ individuals could naturally also harbour low viral reservoirs.MethodsWe screened 451 HIV-1-infected treated-individuals with suppressed plasma viremia for at least 3 years and stored cryopreserved peripheral blood mononuclear cells (PBMCs). Total HIV-DNA was analysed in PBMCs with ddPCR. Individuals with <50 HIV-DNA copies/106 PBMCs constitute the ‘Low Viral Reservoir Treated’ cohort (LoViReT). Longitudinal samples were obtained from 12 chronically treated LoViReT and compared to 13 controls (>50 HIV-DNA copies/106 PBMCs) to analyse total HIV-DNA, T-cell and NK-cell populations, HIV-1 specific antibodies, and plasma inflammation markers.FindingsWe found that 9.3% of the individuals screened had <50 HIV-DNA copies/106 PBMCs. At least 66% initiated cART during the chronic phase of HIV-1 infection (cp-LoViReT). Cp-LoViReT harboured lower levels of HIV-DNA before cART and after treatment introduction the decays were greater compared to controls. They displayed a marked decline in quantity and avidity in HIV-specific antibodies after initiation of cART. Cp-LoViReT had fewer CD8+ TTM and TEMRA in the absence of cART, and higher CD8+ TN after 18 months on therapy.InterpretationTreated chronically HIV-1-infected LoViReT represent a new phenotype of individuals characterized by an intrinsically reduced viral reservoir, less impaired CD8+ T-cell compartment before cART, and low circulating HIV-1 antigens despite being treated in the chronic phase of infection. The identification of this unique group of individuals is of great interest for the design of future eradication studies.FundingMSD Spain

Considerations on nosology for HIV-associated neurocognitive disorders: it is time to update?

The prognosis and the clinical manifestations of HIV infection have changed with the introduction of the potent combination antiretroviral therapy (cART); however, up to 50% of patients meet research criteria for "HIV-associated neurocognitive disorders" (HAND) according with current nosology. The majority of patients affected by HAND, especially in cohorts with suppressed plasma viremia, showed an Asymptomatic Neurocognitive Impairment (ANI), without any functional impairment. After more than 10years from the introduction of the current so-called "Frascati criteria", this mini-review aimed to address the emerging limitations in current diagnosis procedures. We discussed the most relevant literature on HAND prevalence, etiology, and diagnosis. We addressed three main emerging issues: (1) the unclear clinical relevance of ANI entity; (2) the evidences that Frascati criteria could produce a significant overestimation of HAND; (3) the need to better identify patients with a higher risk to develop HAND requiring routine neuropsychological examinations. Frascati criteria should be updated to better respond to the present characteristics of HIV + cohorts and to help clinicians in their cognitive and global management.

A Phase I, Randomized, Controlled Clinical Study of CC-11050 in People Living With HIV With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE).

Phosphodiesterase 4 inhibitors (PDE4i) are novel anti-inflammatory medications that have been approved for rheumatologic diseases and have been tested as host-directed therapy in tuberculosis. We examined the safety of CC-11050, a potent PDE4i in people living with HIV (PLWH) with suppressed HIV plasma viremia. We hypothesized that CC-11050 could be used to modulate HIV-related inflammation. Thirty PLWH on antiretroviral therapy (ART) ≥ 1 year with suppressed HIV viremia were enrolled and randomized 2:1 to 12 weeks of CC-11050 200mg twice daily or placebo with follow-up at weeks 2, 4, 8, 12, and 16. Primary endpoint was safety. Secondary endpoints were the effect of CC-11050 on cytokines, monocyte, and T-cell activation and potential pharmacokinetic interaction between CC-11050 and Efavirenz (EFV). At baseline, median age was 49.5 years and CD4 count 459 cells/µL. Most frequent adverse events (grade 1 and 2 only) in CC-11050 group were headache, diarrhea, nausea, cough, nasal congestion, and restlessness. Over a 12-week period, the CC-11050 group had lower level of IL-8, adjusted for baseline level, group, and week (0.72-fold, P = .02), lower percentage of NK cells (0.87-fold, P = .02) and higher IL-6 level (1.48-fold, P = .03) compared to placebo (0.87-fold, P = .02). CC-11050 and EFV co-administration did not reveal any pharmacokinetic interaction. CC-11050 was well tolerated in PLWH, without affecting CD4 counts or plasma viremia, and led to a decrease in NK cells and plasma IL-8 level after 12-weeks of administration. Further study will be needed to elucidate the efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy in HIV.

A phase 1, randomized, controlled clinical study of CC-11050 in people living with HIV with suppressed plasma viremia on antiretroviral therapy (APHRODITE)

Abstract Background Phosphodiesterase 4 inhibitors (PDE4i) block the degradation of cyclic adenosine monophosphate and modulate both innate and adaptive immune responses. PDE4i have been approved for rheumatologic diseases and tested as host-directed therapy in TB. We examined the safety of CC-11050, a new potent PDE4i, in HIV+ people with suppressed viral load (VL). We hypothesized that CC-11050 could be used to modulate HIV-related inflammatory responses. Methods Thirty HIV+ participants, on antiretroviral therapy (ART) ≥ 1 year with HIV VL &amp;lt;50 copies/mL were randomized 2:1 to 12 weeks of CC-11050 200mg BID or placebo with follow-up at weeks 2, 4, 8, 12 and 16. Primary endpoint was safety. We also assessed the effect of CC-11050 on CD4+, CD8+, NK, VL, plasma cytokines, monocyte and T-cell activation. Results At baseline, median age was 49.5 years and CD4+ 459 cells/μL. Most frequent adverse events (only grades 1–2) in CC-11050 group were headache, diarrhea, nausea, cough and nasal congestion. The CC-11050 group had lower IL-8 level after adjustment for baseline level, group and week (0.72 fold, p=0.02) and lower %NK cells compared to placebo (0.87 fold, p=0.02). At week 12, the CC-11050 group had higher %CD14++CD16+ monocytes than placebo (median 58.5% vs 50.7%, p=0.03). There was no significant effect on plasma HIV viremia, assessed by single copy assay and on cell-associated DNA and RNA in PBMC. Conclusions CC-11050 was well tolerated in HIV+ participants without affecting controlled viremia. CC-11050 had an effect on innate immune mechanisms, by decreasing NK cells and IL-8 level and increasing intermediate monocytes. Further study is needed to elucidate the efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy in HIV.

CNS HIV virus persistence irrespective of CD4 T cell trafficking

Abstract Incomplete HIV virologic suppression in the central nervous system (CNS) can cause persisting neurologic disorders even with suppressed plasma viremia. To better understand immune properties that support CNS virus persistence we characterized T cells and virus genotypes from cerebrospinal fluid (CSF) of HIV-infected participants to understand local cell trafficking behavior and the influence of combination antiretroviral therapy (ART). Compared to blood, CSF T cells expressed higher frequencies of CCR5****, CD69****, CX3CR1****, CD39**, and HLADR**(P values:*≤0.05, **≤0.01, ***≤0.001,****≤0.0001). Among CSF T cells, CD4 T cells were more likely to express CCR7****, CX3CR1****, and CD39**, and less likely to express CCR5*. CX3CR1 expression on CSF CD4 T cells correlated with CSF viral load (VL)*, whereas, CD39 expression mirrored CSF** and plasma VL*. In the absence of ART, CSF HIV (VL&amp;gt;900 copies/mL) shared majority sequence similarity to plasma virus demonstrating a migratory influence of susceptible cells into the CNS. However, CSF CD4 T cells from persons on ART expressed decreased CCR5**, CX3CR1****, HLADR****, and CD39***, regardless of viral suppression, while matched-PBMC CD4 T cells did not exhibit these trends. CSF CD4 T cells expressed features consistent with immune-restricted localization but with a migratory profile indicative of immune surveillance function and lymphoid trafficking. ART use associated with reduced migratory properties regardless of CNS viremia, suggesting ongoing CNS HIV replication under therapy involves local susceptible cells distinct from circulation. This CSF cellular profile could serve as a reference to target biomedical interventions that improve HIV suppression in the CNS.

Genetic diversity in the env V1-V2 region of proviral quasispecies from long-term controller MHC-typed cynomolgus macaques infected with SHIVSF162P4cy.

Intra-host evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) has been shown by viral RNA analysis in subjects who naturally suppress plasma viremia to low levels, known as controllers. However, little is known about the variability of proviral DNA and the inter-relationships among contained systemic viremia, rate of reservoir reseeding and specific major histocompatibility complex (MHC) genotypes, in controllers. Here, we analysed the proviral DNA quasispecies of the env V1-V2 region, in PBMCs and in anatomical compartments of 13 long-term controller monkeys after 3.2 years of infection with simian/human immunodeficiency virus (SHIV)SF162P4cy. A considerable variation in the genetic diversity of proviral quasispecies was present among animals. Seven monkeys exhibited env V1-V2 proviral populations composed of both clusters of identical ancestral sequences and new variants, whereas the other six monkeys displayed relatively high env V1-V2 genetic diversity with a large proportion of diverse novel sequences. Our results demonstrate that in SHIVSF162P4cy-infected monkeys there exists a disparate pattern of intra-host viral diversity and that reseeding of the proviral reservoir occurs in some animals. Moreover, even though no particular association has been observed between MHC haplotypes and the long-term control of infection, a remarkably similar pattern of intra-host viral diversity and divergence was found within animals carrying the M3 haplotype. This suggests that in animals bearing the same MHC haplotype and infected with the same virus, viral diversity follows a similar pattern with similar outcomes and control of infection.

Adipose Tissue in HIV Infection.

HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal-vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV-associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR-γ and other regulatory gene expression, and increased proinflammatory cytokine production. Newer-generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage. © 2017 American Physiological Society. Compr Physiol 7:1339-1357, 2017.

High Cellular Monocyte Activation in People Living With Human Immunodeficiency Virus on Combination Antiretroviral Therapy and Lifestyle-Matched Controls Is Associated With Greater Inflammation in Cerebrospinal Fluid.

BackgroundIncreased monocyte activation and intestinal damage have been shown to be predictive for the increased morbidity and mortality observed in treated people living with human immunodeficiency virus (PLHIV).MethodsA cross-sectional analysis of cellular and soluble markers of monocyte activation, coagulation, intestinal damage, and inflammation in plasma and cerebrospinal fluid (CSF) of PLHIV with suppressed plasma viremia on combination antiretroviral therapy and age and demographically comparable HIV-negative individuals participating in the Comorbidity in Relation to AIDS (COBRA) cohort and, where appropriate, age-matched blood bank donors (BBD).ResultsPeople living with HIV, HIV-negative individuals, and BBD had comparable percentages of classical, intermediate, and nonclassical monocytes. Expression of CD163, CD32, CD64, HLA-DR, CD38, CD40, CD86, CD91, CD11c, and CX3CR1 on monocytes did not differ between PLHIV and HIV-negative individuals, but it differed significantly from BBD. Principal component analysis revealed that 57.5% of PLHIV and 62.5% of HIV-negative individuals had a high monocyte activation profile compared with 2.9% of BBD. Cellular monocyte activation in the COBRA cohort was strongly associated with soluble markers of monocyte activation and inflammation in the CSF.ConclusionsPeople living with HIV and HIV-negative COBRA participants had high levels of cellular monocyte activation compared with age-matched BBD. High monocyte activation was predictive for inflammation in the CSF.

A Prospective Cohort Study of Neurocognitive Function in Aviremic HIV-Infected Patients Treated With 1 or 3 Antiretrovirals

The evolution of neurocognitive performance in aviremic human immunodeficiency virus (HIV)-positive patients treated with <3 antiretrovirals is unknown. We prospectively included aviremic (≥1 year) HIV-positive patients, without concomitant major neurocognitive confounders, currently receiving boosted lopinavir or darunavir as monotherapy (n = 67) or triple antiretroviral therapy (ART) (n = 67) for ≥1 year. We evaluated neurocognitive function (7 domains) at baseline and after 1 year. We performed analysis of covariance to evaluate if 1 additional year of exposure to monotherapy compared with triple ART had an effect on Global Deficit Score (GDS) changes after adjustment for potential confounders. We also compared the evolution of neurocognitive performance and impairment rates. Intention-to-treat analysis showed that monotherapy did not influence 1-year GDS change after adjustment for significant confounders (age, ethnicity, duration of therapy, hepatitis C virus status, and HOMA-IR index); the adjusted effect was -0.04 (95% confidence interval, -.14 to .05; P = .38). Neurocognitive stability was observed with monotherapy and triple therapy (GDS crude mean change, -0.09 [95% confidence interval, -.16 to -.01] vs -0.08 [-.14 to -.02]), after 1 year of follow-up, similar proportions of patients changed neurocognitive status from impaired to unimpaired (monotherapy, 4 of 18 [22.2%]; triple therapy, 4 of 19 [21.1%]; P = .91) and vice versa (monotherapy, 5 of 44 [10.2%] and triple therapy, 3 of 45 [6.3%]; P = .48). Similar results were observed in an on-treatment analysis and with use of clinical ratings instead of GDS changes. The number of antiretrovirals included in the ART regimen does not seem to influence the evolution of neurocognitive function in HIV-infected patients with suppressed plasma viremia.

The ecological deficit

The almost complete extinction of small mammals in forest islands within 25 years of the construction of a reservoir that fragmented the habitat provides a striking example of delayed biodiversity loss. Two papers published this week test the new generation of broad and potent anti-HIV1 monoclonal antibodies (mAbs) in primate models with promising results, both concluding that their results strongly encourage the investigation of mAb therapy for HIV-1 in humans. Dan Barouch et al. show that a single infusion of the potent, broadly neutralizing anti-HIV-1 antibody PGT121, as well as various mAb cocktails, suppress the virus to undetectable levels in just a week in SHIV-infected rhesus monkeys. Masashi Shingai et al. report that co-administration of the antibodies 3BNC117 and 10-1074 results in potent suppression of plasma viraemia lasting for several weeks in chronically SHIV-infected macaques.

Antibodies advance the search for a cure

Efforts to make a prophylactic HIV vaccine have identified monoclonal antibodies that potently suppress viral replication. Studies in monkeys show that these reagents effectively treat HIV infection. See Article p.224 & Letter p.277 Two papers published this week test the new generation of broad and potent anti-HIV1 monoclonal antibodies (mAbs) in primate models with promising results, both concluding that their results strongly encourage the investigation of mAb therapy for HIV-1 in humans. Dan Barouch et al. show that a single infusion of the potent, broadly neutralizing anti-HIV-1 antibody PGT121, as well as various mAb cocktails, suppress the virus to undetectable levels in just a week in SHIV-infected rhesus monkeys. Masashi Shingai et al. report that co-administration of the antibodies 3BNC117 and 10-1074 results in potent suppression of plasma viraemia lasting for several weeks in chronically SHIV-infected macaques.

HIV-1 Nef Sequence and Functional Compartmentalization in the Gut Is Not Due to Differential Cytotoxic T Lymphocyte Selective Pressure

The gut is the largest lymphoid organ in the body and a site of active HIV-1 replication and immune surveillance. The gut is a reservoir of persistent infection in some individuals with fully suppressed plasma viremia on combination antiretroviral therapy (cART) although the cause of this persistence is unknown. The HIV-1 accessory protein Nef contributes to persistence through multiple functions including immune evasion and increasing infectivity. Previous studies showed that Nef’s function is shaped by cytotoxic T lymphocyte (CTL) responses and that there are distinct populations of Nef within tissue compartments. We asked whether Nef’s sequence and/or function are compartmentalized in the gut and how compartmentalization relates to local CTL immune responses. Primary nef quasispecies from paired plasma and sigmoid colon biopsies from chronically infected subjects not on therapy were sequenced and cloned into Env− Vpu− pseudotyped reporter viruses. CTL responses were mapped by IFN-γ ELISpot using expanded CD8+ cells from blood and gut with pools of overlapping peptides covering the entire HIV proteome. CD4 and MHC Class I Nef-mediated downregulation was measured by flow cytometry. Multiple tests indicated compartmentalization of nef sequences in 5 of 8 subjects. There was also compartmentalization of function with MHC Class I downregulation relatively well preserved, but significant loss of CD4 downregulation specifically by gut quasispecies in 5 of 7 subjects. There was no compartmentalization of CTL responses in 6 of 8 subjects, and the selective pressure on quasispecies correlated with the magnitude CTL response regardless of location. These results demonstrate that Nef adapts via diverse pathways to local selective pressures within gut mucosa, which may be predominated by factors other than CTL responses such as target cell availability. The finding of a functionally distinct population within gut mucosa offers some insight into how HIV-1 may persist in the gut despite fully suppressed plasma viremia on cART.

Robust suppression of env‐SHIV viremia in Macaca nemestrina by 3‐drug ART is independent of timing of initiation during chronic infection

Nonhuman primates (NHPs) are an important model organism for studies of HIV pathogenesis and preclinical evaluation of anti-HIV therapies. The successful translation of NHP-derived data to clinically relevant anti-HIV studies will require better understanding of the viral strains and NHP species used and their responses to existing antiretroviral therapies (ART). Five pigtailed macaques (Macaca nemestrina) were productively infected with the SIV/HIV chimeric virus SHIV-1157 ipd3N4 following intravenous challenge. After 8 or 27 weeks, ART (PMPA, FTC, raltegravir) was initiated. Viral load, T-cell counts, and production of SHIV-specific antibodies were monitored throughout the course of infection and ART. ART led to a rapid and sustained decrease in plasma viral load. Suppression of plasma viremia by ART was independent of the timing of initiation during chronic infection. We present a new NHP model of HIV infection on antiretroviral therapy, which should prove applicable to multiple clinically relevant anti-HIV approaches.

Seminal Human Immunodeficiency Virus Blips and Structured Natural Conception In Serodiscordant Couples

TO THE EDITOR—As the prognosis for human immunodeficiency virus (HIV)– infected patients has improved with effective therapies, the prospect of raising children has become a realistic expectation among many serodiscordant couples. For seronegative women, structured natural conception can offer an appealing (and affordable) balance between getting pregnant and avoiding infection from their seropositive male partner. However, despite sustained long-term suppression of plasma viremia by antiretroviral therapy below the level of detection, some HIV-infected men intermittently and unpredictably have detectable free or cell-associated HIV in their semen, independent of drug regimen or seminal drug levels [1–4]. Shedding has been associated with transient increases in T-cell activation confined to the male genital tract [4–6]. The finite (albeit quite small) possibility of infecting a seronegative partner during intercourse even when the seropositive patient has plasma virus fully suppressed looms over structured natural conception initiatives for discordant heterosexual couples wanting offspring [1, 7, 8]. Unfortunately, an absolute zero risk for a coital act seems theoretically unattainable, given the limitations of current interventions, since elimination of cellassociated HIV is not yet achievable [9]. Integrated proviral DNA lies dormant in compartmentalized cellular reservoirs, prominently including the neurological and genitourinary compartments. When HIV-harboring cells within a compartment are stimulated, site-specific viral blips occur irrespective of systemic events in blood and elsewhere. Restricted by their specific mechanism of action, drugs targeting isolated intracellular steps in the preintegration viral life cycle cannot interfere with release of virus during the first ensuing cycle after activation [10]. Even when pregnancy is the goal, unprotected intercourse should be avoided in the presence of recognized sexually transmitted diseases or other genitourinary infections; however, self-limited productive HIV infection is likely more often triggered by subclinical and, thus, unsuspected inflammation (such as asymptomatic shedding of herpesviruses) [5, 6, 11, 12]. The very small residual risk of HIV transmission associated with structured natural conception may be acceptable to qualifying and well-informed couples (especially when other options are unavailable or impractical), but the ultimate decision maker must always be the unharassed female partner [13–15].

Attenuation of multiple Nef functions in HIV-1 elite controllers

BackgroundImpaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; however, activity of the accessory protein Nef remains incompletely characterized. We examined the ability of 91 Nef clones, isolated from plasma of 45 EC and 46 chronic progressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariant chain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC.ResultsIn general, EC Nef clones were functional; however, all five activities were significantly lower in EC compared to CP. Nef clones from HLA-B*57-expressing EC exhibited poorer CD4 down-regulation function compared to those from non-B*57 EC, and the number of EC-specific B*57-associated Nef polymorphisms correlated inversely with 4 of 5 Nef functions in these individuals.ConclusionResults indicate that decreased HIV-1 Nef function, due in part to host immune selection pressures, may be a hallmark of the EC phenotype.

HIV reservoirs

Plasma HIV viremia can be suppressed and maintained below the limits of detection for prolonged periods of time in the vast majority of HIV-infected individuals who receive antiretroviral therapy (ART). Thus, the clinical outcome for HIV-infected individuals who have access to these drugs is dramatically improved. However, ART alone cannot eradicate HIV in infected individuals and this impediment is likely in part due to the persistence of viral reservoirs in the peripheral blood and lymphoid tissues of infected individuals despite the suppression of plasma viremia. In recent years, major research efforts have been dedicated to a better understanding of the pathogenesis of persistent HIV infection and to the development of therapeutic strategies aimed at eradicating virus in infected individuals receiving ART. In this review, we discuss the pathophysiology of CD4 T-cell HIV reservoirs, including recent advances in our understanding of the mechanisms of persistent viral infection and perspectives for eradication of HIV in infected individuals.

Discontinuation of Pneumocystis jirovecii Pneumonia Prophylaxis with CD4 Count &lt;200 Cells/µL and Virologic Suppression: A Systematic Review

BackgroundHIV viral load (VL) is currently not part of the criteria for Pneumocystis jirovecii pneumonia (PCP) prophylaxis discontinuation, but suppression of plasma viremia with antiretroviral therapy may allow for discontinuation of PCP prophylaxis even with CD4 count <200 cells/µL.MethodsA systematic review was performed to determine the incidence of PCP in HIV-infected individuals with CD4 count <200 cells/µL and fully suppressed VL on antiretroviral therapy but not receiving PCP prophylaxis.ResultsFour articles examined individuals who discontinued PCP prophylaxis with CD4 count <200 cells/µL in the context of fully suppressed VL on antiretroviral therapy. The overall incidence of PCP was 0.48 cases per 100 person-years (PY) (95% confidence interval (CI) (0.06–0.89). This was lower than the incidence of PCP in untreated HIV infection (5.30 cases/100 PY, 95% CI 4.1–6.8) and lower than the incidence in persons with CD4 count <200 cells/µL, before the availability of highly active antiretroviral therapy (HAART), who continued prophylaxis (4.85/100 PY, 95% CI 0.92–8.78). In one study in which individuals were stratified according to CD4 count <200 cells/µL, there was a greater risk of PCP with CD4 count ≤100 cells/µL compared to 101–200 cells/µL.ConclusionPrimary PCP prophylaxis may be safely discontinued in HIV-infected individuals with CD4 count between 101–200 cells/µL provided the VL is fully suppressed on antiretroviral therapy. However, there are inadequate data available to make this recommendation when the CD4 count is ≤100 cells/µL. A revision of guidelines on primary PCP prophylaxis to include consideration of the VL is merited.