Untreated HIV Infection Research Articles

Measuring the Unknown

Measuring the Unknown

The natural history of HIV infection

Purpose of reviewTo review recent published literature around three areas: long-term nonprogression/viral control; predictors of viral load set point/disease progression; and the potential impact of antiretroviral therapy (ART) in early HIV infection.Recent findingsThe natural course of untreated HIV infection varies widely with some HIV-positive individuals able to maintain high CD4 cell counts and/or suppressed viral load in the absence of ART. Although similar, the underlying mechanistic processes leading to long-term nonprogression and viral control are likely to differ. Concerted ongoing research efforts will hopefully identify host factors that are causally related to these phenotypes, thus providing opportunities for the development of novel treatment or preventive strategies. Although there is increasing evidence that initiation of ART during primary infection may prevent the immunological deterioration which would otherwise be seen in untreated HIV infection, recent studies do not address the longer term clinical benefits of ART at this very early stage.SummaryA better understanding of the relative influences of viral, host, and environmental factors on the natural course of HIV infection has the potential to identify novel targets for intervention to prevent and treat HIV-infected persons.

HIV: An underrecognized secondary cause of osteoporosis?

HIV: An underrecognized secondary cause of osteoporosis?

The effect of HIV infection on atherosclerosis and lipoprotein metabolism: A one year prospective study

ObjectivesHIV infection is associated with dyslipidaemia and increased risk of cardiovascular disease. The effects of HIV infection and antiretroviral treatment on surrogate markers of atherosclerosis, and lipoprotein metabolism were evaluated in a 12 month prospective study. Methods and resultsTreatment-naive HIV patients were recruited into one of three groups: untreated HIV infection not likely to require initiation of antiretroviral therapy (ART) for at least 12 months; initiating treatment with non nucleoside reverse transcriptase inhibitor-containing ART regimen and initiating treatment with protease inhibitor-containing ART regimen. The patients underwent assessment of carotid intima-media thickness (cIMT), pulse wave velocity (PWV), brachial flow-mediated dilation (FMD) and variables of plasma lipoprotein metabolism at baseline and 12 months. The findings were compared with published values for age and sex matched HIV-negative healthy subjects in a cross-sectional fashion. cIMT and FMD were lower while PWV was higher in HIV-patients compared with HIV-negative individuals; none of the markers changed significantly during 12 months follow up. HIV patients had hypoalphalipoproteinemia and elevated plasma levels of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein. The only significant changes in lipid-related variables were elevation of total cholesterol and triglycerides in patients treated with PI-containing regimen and elevation of plasma LCAT levels in patients treated with NNRTI-containing regimen. The ability of whole and apoB-depleted plasma to effect cholesterol efflux was not impaired in all three groups. ConclusionsThis study did not find evidence for rapid progression of subclinical atherosclerosis and deterioration of dyslipidaemia in HIV patients within 1 year.

Herpes Simplex Virus Type 2 Coinfection Does Not Accelerate CD4 Count Decline in Untreated HIV Infection

Herpes simplex virus type 2 (HSV-2) reactivations are associated with increased HIV load, but whether HSV-2 coinfection accelerates HIV disease is unclear. We compared rates of CD4 count decline according to HSV-2 status in untreated HIV-infected adults. HIV-infected patients with a past period of antiretroviral therapy (ART)-untreated follow-up with initial CD4 count of 400-900 cells/mm(3) and no chronic anti-HSV therapy were included. HSV-2 status was determined by HerpeSelect enzyme-linked immunosorbent assay. Rates of CD4 count change were compared by HSV-2 status using mixed linear regression models, and time to the first of ART initiation or CD4 <350 cells/mm(3) using proportional hazards models. Of 218 patients included, 123 (56.4%) were seropositive for HSV-2 and 161 (73.8%) for HSV-1. In univariate analysis, the difference in the rate of CD4 count change associated with HSV-2 was not statistically significant at +13.6 cells/mm(3)/year (P = .12). Results were similar at -4.5 cells/mm(3)/year (P = .68) after adjustment for sex, HSV type 1, oral and genital herpes symptoms, immigrant status, and the interaction of immigrant status with time. However, HSV-2 seropositivity was associated with a shorter time to the first of ART initiation or CD4 <350 cells/mm(3), with an adjusted hazard ratio of 2.07 (95% confidence interval, 1.28-3.33). HSV-2 coinfection was not associated with the rate of CD4 count decline during ART-untreated HIV infection, but was associated with an earlier combined endpoint of ART initiation or CD4 <350 cells/mm(3). Attenuating effects of acyclovir on HIV disease progression observed in recent clinical trials may result from direct anti-HIV activity rather than indirect benefits from HSV-2 suppression.

Vγ2Vδ2 T Cells are Skewed Toward a Terminal Differentiation Phenotype in Untreated HIV Infection

Vγ2Vδ2 T Cells are Skewed Toward a Terminal Differentiation Phenotype in Untreated HIV Infection

Grade 3 Anal Intraepithelial Neoplasia in an HIV-infected African Girl

Women with HIV infection are at increased risk of anogenital dysplasia and cancer, related to human papillomavirus infection. These neoplasms are rare in perinatally HIV-infected girls before onset of sexual activity. We report a case of high-grade anal dysplasia in a 10-year-old African girl with untreated perinatal HIV infection.

Interferon-α Is the Primary Plasma Type-I IFN in HIV-1 Infection and Correlates with Immune Activation and Disease Markers

Type-I interferon (IFN-I) has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFNα in HCV-infected subjects to model the effect of IFNα on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012), and IFNα was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001). IFNα was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFNα mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFNα in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003) and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009). In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003). These studies identify IFNα derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection.

Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial

In countries with a high incidence of HIV and tuberculosis co-infection, nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs. We aimed to compare efficacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in co-infected patients. We did a multicentre, open-label, randomised, non-inferiority trial at three health centres in Maputo, Mozambique. We enrolled adults (≥18 years) with tuberculosis and previously untreated HIV infection (CD4 cell counts <250 cells per μL) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal. 4-6 weeks after the start of tuberculosis treatment, we randomly allocated patients (1:1) with central randomisation, block sizes of two to six, and stratified by site and CD4 cell count to nevirapine (200 mg twice daily) or efavirenz (600 mg once daily), plus lamivudine and stavudine. The primary endpoint was virological suppression at 48 weeks (HIV-1 RNA <50 copies per mL) in all patients who received at least one dose of study drug (intention-to-treat population); death and loss to follow-up were recorded as treatment failure. The non-inferiority margin for the difference of efficacy was 10%. We assessed efficacy in intention-to-treat and per-protocol populations and safety in all patients who received study drug. This study is registered with ClinicalTrials.gov, number NCT00495326. Between October, 2007, and March, 2010, we enrolled 285 patients into each group. 242 (85%) patients in the nevirapine group and 233 (82%) patients in the efavirenz group completed follow-up. In the intention-to-treat population, 184 patients (64·6%, 95% CI 58·7-70·1) allocated nevirapine achieved virological suppression at week 48, as did 199 patients (69·8%, 64·1-75·1) allocated efavirenz (one-sided 95% CI of the difference of efficacy 11·7%). In the per-protocol population, 170 (70·0%, 63·8-75·7) of 243 patients allocated nevirapine achieved virological suppression at week 48, as did 194 (78·9%, 73·2-83·8) of 246 patients allocated efavirenz (one-sided 95% CI 15·4%). The median CD4 cell count at randomisation was 89 cells per μL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine. 20 patients allocated nevirapine (7%) had grade 3-4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz (6%). Three patients had severe rash after receipt of nevirapine (1%) but no patients did after receipt of efavirenz. 18 patients in the nevirapine group died, as did 17 patients in the efavirenz group. Although non-inferiority of the nevirapine-regimen was not shown, nevirapine at full dose could be a safe, acceptable alternative for patients unable to tolerate efavirenz. French Research Agency for HIV/AIDS and hepatitis (ANRS).

Changes in Biomarkers of Liver Disease during Successful Combination Antiretroviral Therapy in HIV–HCV-Coinfected Individuals

We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals. Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment. Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes. Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

A young woman with HIV and hemiparesis

Progressive Multifocal Leucoencephalopathy (PML) is a rare and invariably fatal neurological disease that is seen patients with untreated HIV infection and as a complication of immune suppression with agents such as natalizumab. With the increasing occurrence of HIV, it is important to consider this condition in the differential diagnosis of patients with neurological features. We present the case of a young woman with a long history of HIV infection who presented with neurological symptoms; recognition of this diagnosis enabled identification of her poor compliance with treatment. The investigation and treatment of this condition is discussed.

Posterior Reversible Encephalopathy Syndrome in a Patient with Newly Diagnosed HIV Infection and End Stage Renal Disease

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome in which patients present with an acute or subacute clinical presentation of seizures, visual disturbances, headache, and altered mental status. The pathophysiology of PRES may be explained by endothelial dysfunction that leads to transudation of fluids and protein, resulting in vasogenic cerebral edema. PRES is typically associated with many conditions such as hypertension, uremia, immunosuppressive drugs, and sepsis. This is a case report of a 39-year-old woman with untreated HIV infection and end-stage renal disease (ESRD) who developed PRES with a normal blood pressure and no other known causes of PRES. Untreated HIV is associated with known endothelial dysfunction and we believe that this, in combination with her untreated end-stage renal disease, contributed to her unique presentation of PRES. Although uncommon in HIV-infected patients and challenging to diagnose, prompt recognition of PRES is critical to provide appropriate care and ensure reversibility of the vasogenic edema seen in PRES.

Modulation of LPS-Induced CD4+ T-Cell Activation and Apoptosis by Antioxidants in Untreated Asymptomatic HIV Infected Participants: AnIn VitroStudy

Persistent immune activation characterises HIV infection and is associated with depletion of CD4+ T-cells and increased risk of disease progression. Early loss of gut mucosal integrity results in the translocation of microbial products such as lipopolysaccharide (LPS) into the systemic circulation. This is an important source of on-going immune stimulation. The purpose of this study was to determine levels of CD4+ T-cell activation (%CD25 expression) and apoptosis (% annexin V/7-AAD) in asymptomatic, untreated HIV infection at baseline and after stimulation with LPS and incubation with or without vitamin C and N-acetylcysteine. LPS induced a significant (P < 0.03) increase in %CD25 expression, annexin V, and 7-AAD in HIV positive individuals. NAC in combination with vitamin C, significantly (P = 0.0018) reduced activation and early apoptosis of CD4+ T-cells to a greater degree than with either antioxidant alone. Certain combinations of antioxidants could be important in reducing the harmful effects of chronic immune activation and thereby limit CD4+ T-cell depletion. Importantly, we showed that CD4+ T-cells of the HIV positive group responded better to a combination of the antioxidants at this stage than those of the controls. Therefore, appropriate intervention at this asymptomatic stage could rescue the cells before repetitive activation results in the death of CD4+ T-cells.

Serum Adenosine Deaminase and Total Immunoglobulin G Correlate with Markers of Immune Activation and Inversely with CD4 Counts in Asymptomatic, Treatment-Naive HIV Infection

HIV-infection is characterized by aberrant immune activation and ongoing inflammation. Markers of inflammation are now recognized to have prognostic value for adverse events, independent of viral loads and CD4 counts. This study aimed to delineate a panel of affordable markers of immune activation in untreated HIV-infection that may have an impact on the management of HIV in resource-limited settings. This was a cross-sectional study of 86 untreated newly diagnosed HIV-infected patients and 54 matched controls attending a voluntary testing clinic in Cape Town, South Africa. Serum levels of adenosine deaminase (ADA), total immunoglobulin G (IgG), soluble CD14 and lipopolysaccharide-binding protein (LBP) were measured and correlated with CD4 counts, viral loads and expression of CD38 on CD8+ T cells. ADA, IgG and LBP were all significantly increased in the HIV infected group (p < 0.0001) compared with uninfected controls. Soluble CD14 was also significantly increased (p = 0.0187). Furthermore, all these parameters correlated inversely with CD4 counts (r = -0.481 p < 0.0001; r = -0.561; p < 0.0001; r = -0.387 p = 0.0007 and r = -0.254 p = 0.0240, respectively). Only ADA correlated with viral load (r = 0.260 p = 0.0172). Importantly, ADA, IgG and LBP correlated directly with %CD38 on CD8+ T cells (r = 0.369 p < 0.0001; r = 0.284 p = 0.001; r = 0.408 p = 0.0006, respectively). Affordable parameters such as serum ADA and IgG correlated significantly with immune activation levels and markers of disease progression in untreated HIV-infection and therefore may add value to the management of these patients in resource-limited settings.

Plasticity of HIV-specific CD8 T cell responses in untreated HIV-1 infection- a step towards a therapeutic vaccine against drug resistance mutations

Background For a therapeutic HIV-1 vaccine, it should be considered that the immune system has been confronted with a certain viral sequence and mounted CD8 T cell responses specifically towards the infecting virus. One question is whether the immune system of HIV-infected individuals can create a new response towards a variant epitope in the case of vaccination. To study this in a comparable setting, we addressed the question how frequently a new CD8 T cell response can be generated after the occurrence of a viral escape mutation in its recognized epitope in a population not selected for a certain HLA allele. Methods 19 HIV-infected untreated subjects were sampled longitudinally (>6 months. We searched for CD8 T cell responses that declined over the course of untreated infection and sequenced the autologous virus of the early and late time point by RT-PCR. Recognition of wildtype and newly arising sequences was compared in peptide titration assays. Results A total of 30 declining CD8 T cell responses were studied in detail and viral sequence analyses showed amino acid changes in 25 (83%) of these. Peptide titration assays revealed 12 (48%) viral escape mutations with 2 de-novo responses (17%). Here the de-novo response showed less effector functions than the original CD8 T cell response. In addition we identified 5 (20%) shifts in immunodominance. None of the subjects with adaptation to the changing virus carried the HLA alleles B27, B57 or B*5801. Conclusion Our results show that CD8 T cell responses can adapt to the mutations of HIV. However it was limited to only 28% (7 out of 25) of cases in a cohort not expressing protective HLA alleles.

Regulatory B cells are induced in untreated HIV-1 infection and suppress HIV-1 specific T cell responses

Background Regulatory B cells (Breg), the B cells producing interleukin 10 (IL-10), have been identified in mice and humans. Mouse Breg can suppress innate and T cell responses and are implicated in pathogenesis of some autoimmune diseases and immune evasion of some pathogens. However, the role of Breg in humans is less clear. Methods PBMC and gut biopsy samples were obtained from healthy donors and HIV infected individuals. Flow cytometry and Luminex were used to quantify cytokine production. Flow cytometry were used to analyze Breg’s phenotype. Results Breg were elevated in both peripheral blood and gut tissue of untreated HIV-1 infected individuals and the elevation correlated with viral load in early HIV-1 infection. Breg from HIV-1 infected individuals were CD19 + TIM-1 + .Antiretroviral therapy could reduce elevated Breg frequency. Treatment of B cells from healthy donors with microbial translocation products could differentiate them toward a Breg phenotype. Ex vivo Bregs from HIV-1 infected individuals suppressed cytokine production /degranulation of HIV-1 specific T cells that was in part IL-10 dependent. Conclusion

Frequent and strong antibody-mediated NK cell activation to HIV-1 Env in individuals with chronic HIV-1 infection

Background Natural killer (NK) cells are critical in viral control and NK cells that respond to HIV-1 peptides have been described. However, it is unclear how NK cells recognize HIV-1 antigen. We investigated NK cell responses to HIV-1 peptides during early and chronic HIV-1 clade B infection. Methods NK cells responding to HIV-1 peptides were assessed by multiparameter flow cytometry using whole blood from 74 individuals with treated or untreated early or chronic HIV-1 infection. In addition, 15 HIV uninfected individuals were also studied. Results No NK cell responses to HIV-1 peptides were detected in HIV-1 uninfected individuals. The HIV-1 NK cell specific responses to peptide were less frequent during the first year of infection but were of high magnitude and frequent in individuals with controlled or progressive infection (22% vs 79%; P<0.00001). The activation of NK cells to peptide pools required the presence of plasma IgG and the responding NK cells had a low CD16 expression and high CD57 expression. Furthermore, plasma derived from HIV-1 infected individuals was sufficient to trigger a response to HIV-1 Env peptide pool by NK cells from healthy donors suggesting the role of antibodies in mediating this activity. Conclusion NK cell responses to specific antigens can be induced in HIV-1 infection. Large cohorts are needed to assess the consequences of these NK cells against HIV-1 control or protection from infection.

Human intestinal beta defensins inhibit viral replication and are diminished in chronic untreated HIV infection

Background One of the hallmarks of HIV infection is an early and dramatic depletion of CD4 T cells in the intestinal lamina propria. This loss of T cells is accompanied by intestinal epithelial cell disruption resulting in the translocation of luminal bacterial products, persistent systemic immune activation and resultant disease progression. Beta defensins are cationic antimicrobial polypeptides produced by intestinal epithelial cells and phagocytes that are a part of the innate immune response. They have ap ivotal role in maintenance of immune homeostasis in the gut. Although beta defensins have been reported to inhibit bacterial and viral replication in vitro, their role in HIV infection has been incompletely characterized. Methods We investigated anti-viral activity and production of defensins in intestinal mucosal biopsies, stool and plasma from individuals with chronic untreated HIV (chronic progressors), immunologically controlled HIV (elite controllers) and HIV uninfected individuals using ELISA, immunohistochemistry, quantitative PCR and viral inhibition assays. Results Plasma levels of beta defensins were increased in the HIV controller group compared to HIV progressors, whereas levels of beta defensins were significantly decreased in biopsies from chronic progressors. Beta defensin release was induced by HIV in ex vivo cultured intestinal cells. Recombinant beta defensins inhibited HIV replication in vitro. Conclusion Beta defensins are upregulated by HIV and inhibit viral replication in vitro. Chronic progressors, however, had diminished levels of beta defensins in gut biopsies and in the plasma. We propose that beta defensins are induced in HIV infection and have a role in inhibiting viral replication and preventing intestinal epithelial cell disruption. In chronic infection, however, their release is diminished, likely due to epithelial damage in the setting of persistent viremia and mucosal inflammation.

Downregulation of the 5’-ectonucleotidase CD73 of CD8+ CTL of HIV infected patients correlates with immune activation and diminished IL-2 production

Background Chronic untreated HIV infection is immunologically characterized by irreversible loss of CD4+ T cells, general immune activation and CD4+ and CD8+ T cell dysfunction with diminished proliferative capacity. CD73 is an ectoenzyme (5’-ectonucleotidase) expressed on T cells converting 5’-AMP to adenosine, but there is additional evidence of ectonucleotidase-independent CD73 function. Altogether CD73 seems to play a role as a co-stimulatory molecule for T cell differentiation.

Human endogenous retrovirus expression is inversely associated with chronic immune activation in HIV-1 infection.

Human endogenous retroviruses (HERV) are remnants of ancestral retroviral infections integrated into the germ line, and constitute approximately 8% of the genome. Several autoimmune disorders, malignancies, and infectious diseases such as HIV-1 are associated with higher HERV expression. The degree to which HERV expression in vivo results in persistent inflammation is not known. We studied the association of immune activation and HERV-K expression in 20 subjects with chronic, untreated progressive HIV-1 infection and 10 HIV-1 negative controls. The mean HERV-K gag and env RNA expression level in the HIV-1 infected cohort was higher than in the control group (p = 0.0003), and was negatively correlated with the frequency of activated CD38+HLA-DR+CD4+ T cells (Rho = −0.61; p = 0.01) and activated CD38+HLA-DR+CD8+ T cells (Rho = −0.51; p = 0.03). Although HIV-infected persons had higher levels of HERV-K RNA expression (as expected), the level of RNA expression was negatively associated with level of T cell activation. The mechanism for this unexpected association remains to be defined.