Accelerate HIV Disease Progression Research Articles

Dawn of a new beginning- First renal transplant in patient with HIV in Nepal

Human immunodeficiency virus infection was traditionally considered an absolute contraindication for transplantation because of the concern that immunosuppression would accelerate HIV disease progression, resulting in increased mortality and a "waste" of organs. Since potent antiretroviral therapy became widely available in 1996, the prognosis of patients with HIV infection has dramatically improved. HIV-infected patients are now accepted recipients of both HIV-infected and HIV- uninfected donor organs in specialized transplant centers worldwide. However, due to stigma about the disease and lack of appropriate expertise, renal transplant in HIV patients has not been done in Nepal. Here, we report the first case of renal transplantation done in patient with HIV in Nepal. So, even in a resource limited setting like Nepal, HIV-positive ESRD patients with stable disease should be given the benefit of kidney transplantation as patient and graft survival are reasonably good with better quality of life.

Cognition, Coping, and Psychological Distress in HIV.

Interrelationships among HIV-associated neurocognitive dysfunction, avoidant coping, cognitively-oriented coping, and psychological distress were examined using structural equation modelingin an ethnically diverse sample of 209 adults predominantly in the mid-range of illness. Global neurocognitive deficits, assessed with the HIV-dementia scale, were associated with higher levels of avoidant coping, lower levels of cognitive coping, and a higher avoidant/cognitive coping ratio, which were each in turn associated with higher psychological distress measured by a latent factor comprising symptoms of depression, anxiety, and HIV-related distressing thoughts. There were significant indirect effects through avoidant coping and a higher avoidant/cognitive coping ratio. Results suggest the presence ofHIV-associated neurocognitive deficits may interfere withtheutilization of cognitive-based coping strategies andincreasereliance on more maladaptivestrategies,whichin turn may translate to elevated reports ofpsychological distress. Findings may help inform interventions aimed at reducing avoidant coping and psychological distress, two factors associated with accelerated HIVdisease progression.

Ovariectomy Increases CD4 + T cell Activation in Simian Immunodeficiency Virus Infection

People living with HIV (PLWH) have a higher prevalence of alcohol use disorder (AUD), which has been associated with accelerated HIV disease progression. Older PLWH, especially postmenopausal women, are at a greater risk for alcohol-related problems. Previous studies have shown that chronic binge alcohol (CBA) administration leads to higher simian immunodeficiency virus (SIV) loads and accelerated progression towards end-stage disease in rhesus macaques. Clinical studies have shown that ovariectomy (OVX) increases T cell activation and serum TNF-alpha levels. We tested the hypothesis that CBA and ovarian hormone loss, resulting from OVX, increases T cell activation in SIV-infected female rhesus macaques. CBA or isovolumetric water was administered through an intragastric catheter for 30 minutes, 5 days a week, with peak blood alcohol concentrations reaching 50-60 mM. After three months of CBA/VEH administration, macaques were infected with SIVMac251 and 2.5 months later initiated on ART. OVX was performed one month after ART initiation, and study endpoint was ~12 months post-SIV infection. Blood samples obtained at study end point were used for flow cytometry analysis with FITC-CD38, PerCP-CD3, PE-CD45, Qdot 655-CD8, ECD-CD20, APC-Cy7-CD4, PE-Cy7-CD16, APC-CD66, Pacific Blue-CD14, and Am Cyan-Live Dead, using a BD Biosciences LSRII flow cytometer and FlowJo software (version 10.7.1). Two-way ANOVA was used to detect significant differences between groups (N = 7-8/group). At study end-point, there was a main effect of OVX to increase activated CD4+CD38+ T cells (p = 0.0171) compared to SHAM. Neither CBA nor OVX had an effect on activation of CD8+ T cells. There was a main effect of OVX (p = 0.0195) and an interaction (p = 0.05) observed for CD4 T cell numbers (cells/ml). Post-hoc analysis showed higher CD4 T cell number in the CBA/SIV/ART/OVX compared to CBA/SIV/ART/SHAM (p = 0.0174) animals. There were no significant differences between the treatment groups for CD20+, CD14+, and CD16+ cells. Our results show that OVX lead to an increase in activation of peripheral CD4+ T cells and an increase in peripheral CD4+ T cells within CBA animals, which could favor a pro-inflammatory environment and an increase in target cells in SIV-infected female macaques.

Abstract # 2036 Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection

The use of stimulants such as methamphetamine may accelerate HIV disease progression, but scant research has examined stimulant-associated pathophysiologic alterations in treated HIV. In a sample of 55 HIV-positive, methamphetamine-using sexual minority men with a viral load less than 200 copies/mL, 27 participants with a urine sample that was reactive for recent stimulant use (Stimulant Tox+) were compared to 28 who tested negative in urine for stimulants (Stimulant Tox−). Analyses employed the false discovery rate (FDR) under the Benjamini-Hochberg procedure with a 10% cut-off. Stimulant Tox+ participants did not differ from those who were Stimulant Tox− on demographic and clinical characteristics. However, Stimulant Tox+ participants reported more days using methamphetamine in the past 30 days (10.7 versus 4.0; p < 0.01). RNA sequencing provided evidence for differential expression of 32 genes and perturbation of 168 pathways in recent stimulant users. Most notably, we observe upregulation single genes linked to HIV latency (i.e., CD274 and FCGR2A) in Stimulant Tox+ participants. Pathway analyses indicated that recent stimulant use was associated with two-directional perturbation of gene sets governing HIV latency, immune activation, inflammation, neuroendocrine hormone regulation, and neurotransmitter synthesis. Stimulant Tox+ participants also displayed significantly higher log10 TNF-alpha plasma levels (Mean = 1.74 versus 1.63; p = 0.023). Further research is needed to examine these mechanisms whereby stimulant use may contribute to HIV persistence and disease progression.

Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection

Stimulant use may accelerate HIV disease progression through biological and behavioral pathways. However, scant research with treated HIV-positive persons has examined stimulant-associated alterations in pathophysiologic processes relevant to HIV pathogenesis. In a sample of 55 HIV-positive, methamphetamine-using sexual minority men with a viral load less than 200 copies/mL, we conducted RNA sequencing to examine patterns of leukocyte gene expression in participants who had a urine sample that was reactive for stimulants (n = 27) as compared to those who tested non-reactive (n = 28). Results indicated differential expression of 32 genes and perturbation of 168 pathways in recent stimulant users. We observed statistically significant differential expression of single genes previously associated with HIV latency, cell cycle regulation, and immune activation in recent stimulant users (false discovery rate p < 0.10). Pathway analyses indicated enrichment for genes associated with inflammation, innate immune activation, neuroendocrine hormone regulation, and neurotransmitter synthesis. Recent stimulant users displayed concurrent elevations in plasma levels of tumor necrosis factor – alpha (TNF-α) but not interleukin 6 (IL-6). Further research is needed to examine the bio-behavioral mechanisms whereby stimulant use may contribute to HIV persistence and disease progression.

Plasma IP-10 Concentrations Correlate Positively with Viraemia and Inversely with CD4 Counts in Untreated HIV Infection.

Background:Chronic immune activation is a feature of HIV infection associated with accelerated HIV disease progression. There is conflicting data on the association of biomarkers of immune activation with traditional markers of HIV disease progression; CD4 counts and viral load (VL).Objective:The study aimed to determine the association of biomarkers of immune activation; interferon (IFN)-γ-induced protein 10 (IP-10) and soluble cluster of differentiation 14 (sCD14) in chronic HIV infection with traditional markers of HIV disease progression.Methods:We collected demographic data, enumerated CD4 counts and quantified VL in 183 antiretroviral therapy (ART)-naive adults with chronic HIV infection. Plasma concentrations of IP-10 and sCD14 were quantified in the ART-naive adults with chronic HIV infection and 75 HIV-uninfected controls.Results:IP-10 concentrations were significantly higher in the HIV-infected group (median; 257.40pg/ml, IQR; 174.08-376.32) than in the HIV-uninfected (median; 86.19pg/ml, IQR; 67.70-116.39) (P<0.001). Similarly, sCD14 concentrations were significantly higher in the HIV-infected (median; 1.45µg/ml, IQR; 1.02-2.16) group than in the controls (median; 0.89µ/ml, IQR; 0.74-1.18) (P<0.001). High log10 IP-10 concentrations were positively correlated with high log10 viral loads (Spearman’s correlation coefficient [R]=0.21, P=0.003) and inversely correlated with low CD4 counts (R= -0.19, P=0.011). In contrast, log10 sCD14 was not significantly associated with either log10 viral loads (R=0.03, P=0.707) nor CD4 count (R=-0.04, P=0.568).Conclusion:We conclude that plasma sCD14 and IP-10 were elevated in the HIV-infected patients compared to HIV-uninfected individuals possibly due to on-going immune activation. In addition, plasma high concentrations of IP-10 but not sCD14 concentrations are associated with high VL and low CD4 count.

A meta-analysis of HIV and heart rate variability in the era of antiretroviral therapy.

Heart rate variability (HRV) has been used to assess autonomic dysfunction since the beginning of the HIV epidemic. Although autonomic failure was commonly detected in HIV and AIDS patients prior to the advent of antiretroviral therapy (ART), the effect of HIV on HRV in the current era of widespread ART availability is more ambiguous. A systematic search and review was conducted on cross-sectional observational and case-control studies published in the era of ART (1996-2015) that compared HRV between HIV+individuals treated with ART and HIV-controls. Eight out of the 20 studies identified, enrolling a total of 292 HIV+adults (mean age 38.7years) and 201 HIV seronegative controls (mean age 35.1years), were included in a meta-analysis based on stringent methodological criteria. At rest, individuals with HIV showed lower HRV in the time (g)=-0.72, 95% CI (-1.03 to -0.42) and low-frequency (LF) domain (g)=-0.51, (-0.81 to -0.21); markers of lower parasympathetic tone in the time (g)=-0.55, (-0.85 to -0.25) and high-frequency (HF) domain (g)=-0.42, (-0.71 to -0.12); and higher LF:HF ratio (g)=0.46, (0.12-0.86) in the frequency domain, suggestive of parasympathetic withdrawal. This meta-analysis confirmed, within a relatively young cohort of HIV+adults on ART, a general reduction in autonomic function with a shift toward sympathetic dominance. This shift may predispose HIV patients to early and elevated risk of arrhythmias, cardiac events, and accelerated HIV disease progression.

Editorial: HIV and Illicit Drugs of Abuse.

Editorial: HIV and Illicit Drugs of Abuse.

Prevalence of Vitamin B12 and folic acid deficiency in HIV-positive patients and its association with neuropsychiatric symptoms and immunological response.

Deficiency of micronutrients is prevalent even before the development of symptoms of HIV disease and is associated with accelerated HIV disease progression. This study evaluates the prevalence of folate and Vitamin B12 deficiency in HIV-positive patients with or without tuberculosis (TB) and its association with neuropsychiatric symptoms and immunological response. Cross-sectional, observational study in an outpatient setting. Four groups of HIV-positive patients with TB (Group I), HIV-positive patients with neuropsychiatric symptoms (Group II), HIV-positive patients without neuropsychiatric symptoms or TB (Group III), and HIV-negative controls with neuropsychiatric symptoms (Group IV). Vitamin B12 and folate estimation was done using carbonyl metallo-immunoassay method. ANOVA, Kruskal-Wallis and Mann-Whitney, Pearson's correlation. The prevalence of folic acid deficiency was 27.1% in the Group I, 31.9% in the Group II, 23.4% in the Group III, and 32% in the Group IV being higher in patients with neuropsychiatric symptoms in both HIV and non-HIV patients. The prevalence of Vitamin B12 deficiency was 18.8% in Group I, 9.1% in Group II, 4.8% in Group III, and 16.7% in Group IV. The patients with folate deficiency had more severe depression and anxiety. Nearly, 30% of the HIV patients had a folic acid deficiency, and about 10% of the HIV patients had Vitamin B12 deficiency. The folate deficiency was highest among neuropsychiatric patients with or without HIV infection and Vitamin B12 deficiency was higher among HIV patients with TB.

Adiponectin Secretion in HIV-Infected Subjects with or without Antiretroviral Treatment and Illicit Substance Use: Clinical Review and Update

Adiponectin (Acrp30) is a novel polypeptide classified among adipokines that are chiefly secreted by adipocytes within adipose tissue. Besides the adipose tissue, levels of the adipocytokine also circulate in human plasma. Functionally, Acrp30 possesses a primary role in regulation of body fat stores with its anti-inflammatory, glucose and lipid metabolism and weight loss effects. Thus, circulating Acrp30 levels govern obesity and metabolic abnormalities including; dyslipidaemia, cardiovascular disorders and renal disease. A lipodystrophic syndrome including metabolic derangements are common features presenting in HIV-infected patients on antiretroviral therapy (ART). Decreased Acrp30 levels have been documented in lipodystrophic patients as a consequence of adverse effects attributable to various antiretroviral agents. Interestingly, Acrp30 levels are revealed to be suppressed in HIV-infected patients relative to healthy persons even prior to HAART commencement, indicative of HIV infection itself playing a role in Acrp30 dysregulation. On the contrary, circulating Acrp30 levels inversely correlate with body fat composition in healthy non-obese individuals. Thus, lowered Acrp30 concentrations are associated with weight accumulation in obese subjects. More importantly, illicit drug and substance use has been revealed to accelerate HIV disease progression while also impairing Acrp30 production within the adipose tissue. Consequently, these observations collectively portray Acrp30 as a metabolic correlate of adipose tissue inflammation and low fat store during episodes of HIV infection, lypodystrophyic syndrome and illicit substance use. Therapeutic interventions should identify new approaches to restore Acrp30 production and supply during the aforementioned events.

Unhealthy Alcohol Use is Associated with Monocyte Activation Prior to Starting Antiretroviral Therapy.

Alcohol use may accelerate HIV disease progression, but the plausible biological mechanisms have not been clearly elucidated. HIV-positive persons who were not on antiretroviral therapy (ART) completed the baseline assessment for a longitudinal study examining the association of alcohol use with HIV disease markers. Oversampling drinkers, baseline samples were tested for markers of monocyte activation (soluble CD14 [sCD14]), inflammation (interleukin-6 [IL-6]-6), and coagulation (d-dimer). We defined "unhealthy alcohol use" as testing positive using the Alcohol Use Disorders Identification Test-Consumption (≥3 for women and ≥4 for men) in the past 3 months or testing positive using a biomarker of heavy drinking, phosphatidylethanol (≥50 ng/ml). Multiple linear regression was used to examine the associations of unhealthy alcohol use with sCD14, log10 IL-6, and d-dimer. Compared to those who were abstinent from alcohol, unhealthy drinkers had significantly higher sCD14 levels (mean = 1,676 vs. 1,387 ng/ml; mean difference [95% confidence interval (CI)] = 289 [83, 495], p < 0.01). In analyses adjusted for demographic factors, current cigarette smoking, and HIV disease markers, unhealthy drinkers continued to display significantly higher sCD14 levels compared to those who were abstinent from alcohol (adjusted mean = 1,670 vs. 1,406 ng/ml; adjusted mean difference [95% CI] = 264 [47, 480], p = 0.02). Unhealthy alcohol use was not significantly associated with IL-6 or d-dimer levels. Unhealthy alcohol use was independently associated with a marker of monocyte activation (i.e., higher sCD14) that predicts mortality in treated HIV infection. Longitudinal research should examine whether unhealthy alcohol use predicts changes in sCD14 prior to and following ART initiation.

Are long-lasting insecticide-treated bednets and water filters cost-effective tools for delaying HIV disease progression in Kenya?

BackgroundCo-infection with malaria and other infectious diseases has been shown to increase viral load and accelerate HIV disease progression. A recent study in Kenya demonstrated that providing long-lasting insecticide-treated bednets (LLIN) and water filters (WF) to HIV-positive adults with CD4 >350 cells/mm3 significantly reduced HIV progression.DesignWe conducted a cost analysis to estimate the potential net financial savings gained by delaying HIV progression and increasing the time to antiretroviral therapy (ART) eligibility through delivering LLIN and WF to 10% of HIV-positive adults with CD4 >350 cells/mm3 in Kenya.ResultsGiven a 3-year duration of intervention benefit, intervention unit cost of US$32 and patient-year ART cost of US$757 (2011 US$), over the lifetime of ART patients, in Kenya, we estimated the intervention could yield a return on investment (ROI) of 11 (95% uncertainty range [UR]: 5–23), based on a cost of about US$2 million and savings in ART costs of about US$26 million (95% UR: 8–50) (discounted at 3%). Our findings were subjected to a number of sensitivity analyses. Of note, deferral of time to ART eligibility could potentially result in 3,000 new HIV infections not averted by ART and thus decrease ART cost savings to US$14 million, decreasing the ROI to 6.ConclusionsProvision of LLIN and WF could be a cost-saving and practical method to defer time to ART eligibility in the context of highly resource-constrained environments experiencing donor fatigue for HIV/AIDS programs.

HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity.

HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity.

Depression CBT treatment gains among HIV-infected persons with a history of injection drug use varies as a function of baseline substance use

Depression and substance use, the most common comorbidities with HIV, are both associated with poor treatment outcomes and accelerated HIV disease progression. Though previous research has demonstrated short-term and follow-up success for cognitive behavioral therapy for adherence and depression (CBT-AD) on depression outcomes among patients with HIV in care and among patients with HIV in active substance abuse treatment for injection drug use (IDU), there is little information regarding possible moderating effects of active use versus abstinence on depression treatment gains. The present study aimed to examine recent substance use at treatment initiation as a moderator of the acute and maintenance effects of CBT-AD on depression. We used data from a two-arm, randomized controlled trial (N = 89) comparing CBT-AD to enhanced treatment as usual in individuals in treatment for IDU. To test whether depression at time of presentation affected outcomes, repeated-measures ANOVAs were conducted for two time frames: (1) acute phase (baseline to post-treatment) (acute) and (2) maintenance phase (baseline to 12-month follow-up). To further examine maintenance of gains, we additionally looked at post-treatment to 12-month follow-up. Depression scores derived from the clinical global impression for severity and the Montgomery–Asberg depression rating scale (MADRS) served as the primary outcome variables. Acute (baseline post treatment) moderation effects were found for those patients endorsing active drug use at baseline in the CBT-AD condition, who demonstrated the greatest reductions in MADRS scores at post-treatment (F[1,76] = 6.78, p = .01) and follow-up (F[1,61] = 5.46, p = .023). Baseline substance use did not moderate differences from post-treatment to 12-month follow-up as depression treatment gains that occurred acutely from baseline to post-treatment were maintained across both patients engaged in substance use and abstainers. We conclude that CBT-AD for triply diagnosed patients (i.e. HIV, depression, and substance dependence) is useful for treating depression for both patients with a history of substance use, as well as patients currently engaged in substance use.

Pregnancy and HIV disease progression: a systematic review and meta-analysis.

To assess whether pregnancy accelerates HIV disease progression. Studies comparing progression to HIV-related illness, low CD4 count, AIDS-defining illness, HIV-related death, or any death in HIV-infected pregnant and non-pregnant women were included. Relative risks (RR) for each outcome were combined using random effects meta-analysis and were stratified by antiretroviral therapy (ART) availability. 15 studies met the inclusion criteria. Pregnancy was not associated with progression to HIV-related illness [summary RR: 1.32, 95% confidence interval (CI): 0.66-2.61], AIDS-defining illness (summary RR: 0.97, 95% CI: 0.74-1.25) or mortality (summary RR: 0.97, 95% CI: 0.62-1.53), but there was an association with low CD4 counts (summary RR: 1.41, 95% CI: 0.99-2.02) and HIV-related death (summary RR: 1.65, 95% CI: 1.06-2.57). In settings where ART was available, there was no evidence that pregnancy accelerated progress to HIV/AIDS-defining illnesses, death and drop in CD4 count. In settings without ART availability, effect estimates were consistent with pregnancy increasing the risk of progression to HIV/AIDS-defining illnesses and HIV-related or all-cause mortality, but there were too few studies to draw meaningful conclusions. In the absence of ART, pregnancy is associated with small but appreciable increases in the risk of several negative HIV outcomes, but the evidence is too weak to draw firm conclusions. When ART is available, the effects of pregnancy on HIV disease progression are attenuated and there is little reason to discourage healthy HIV-infected women who desire to become pregnant from doing so.

HIV-1 Infection Impairs Regulatory T-Cell Suppressive Capacity on a Per-Cell Basis

The impact of CD4+ regulatory T cells (Tregs) on human immunodeficiency virus type 1 (HIV-1) pathogenesis remains incompletely understood. Although it has been shown that Tregs can be infected with HIV-1, the consequences of infection on a per-cell basis are still unknown. In vitro HIV-GFP infected and noninfected Tregs were isolated by flow-based cell-sorting to investigate Treg suppressive capacity and gene expression profiles. Our data show that HIV-1-infected Tregs were significantly less suppressive than noninfected Tregs and demonstrated down-regulation of genes critical to Treg function. This impaired function may have detrimental consequences for the control of generalized immune activation and accelerate HIV disease progression.

Cocaine Enhances HIV-1–Induced CD4+ T-Cell Apoptosis: Implications in Disease Progression in Cocaine-Abusing HIV-1 Patients

Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1-associated CD4(+) T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4(+) T cells from HIV-1-negative and HIV-1-positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4(+) T cells with cocaine (up to 100 μmol/L concentrations) did not induce apoptosis, but 200 to 1000 μmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4(+) T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4(+) T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4(+) T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1-infected drug abusers.

Herpes simplex virus type 2 and HIV disease progression: a systematic review of observational studies

BackgroundHerpes simplex virus type 2 (HSV-2) is a common co-infection among HIV-infected adults that is hypothesized to accelerate HIV disease progression.MethodsWe searched Medline, EMBASE, relevant conference proceedings (2006–12) and bibliographies of identified studies without language restriction for cohort studies examining the impact of HSV-2 on highly active antiretroviral therapy-untreated HIV disease in adults. The exposure of interest was HSV-2 seropositivity or clinical/laboratory markers of HSV-2 activity. The primary outcome was HIV disease progression, defined as antiretroviral initiation, development of AIDS/opportunistic infection, or progression to CD4 count thresholds (≤200 or ≤350 cells/mm3). Secondary outcomes included HIV plasma viral load and CD4 count.ResultsSeven studies were included. No definitive relationship was observed between HSV-2 seropositivity and time to antiretroviral initiation (n=2 studies), CD4≤350 (n=1), CD4≤200 (n=1), death (n=1), viral load (n=6) or CD4 count (n=3). Although two studies each observed trends towards accelerated progression to clinical AIDS/opportunistic infection in HSV-2 seropositives, with pooled unadjusted hazard ratio=1.85 (95% CI=1.12,3.06; I2=2%), most OIs observed in the study for which data were available can occur at high CD4 counts and may not represent HIV progression. In contrast, a single study HSV-2 disease activity found that the presence of genital HSV-2 DNA was associated with a 0.4 log copies/mL increase in HIV viral load.ConclusionsDespite an observation that HSV-2 activity is associated with increased HIV viral load, definitive evidence linking HSV-2 seropositivity to accelerated HIV disease progression is lacking. The attenuating effects of acyclovir on HIV disease progression observed in recent trials may result both from direct anti-HIV activity as well as from indirect benefits of HSV-2 suppression.

Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction

The contribution of immune activation to accelerated HIV-disease progression in older individuals has not been delineated. Prospective multicenter cohort of older (≥45 years) and younger (18-30 years) HIV-infected adults initiating 192 weeks of antiretroviral therapy (ART). Longitudinal models of CD4 cell restoration examined associations with age-group, thymic volume, immune activation, and viral load. Forty-five older and 45 younger adults (median age 50 and 26 years, respectively) were studied. Older patients had fewer naive CD4 cells (P<0.001) and higher HLA-DR/CD38 expression on CD4 (P=0.05) and CD8 cells (P=0.07) than younger patients at any time on ART. The rate of naive and total CD4 cell increase was similar between age groups, but older patients had a faster mean rate of B-cell increase (by +0.7 cells/week; P=0.01), to higher counts than healthy controls after 192 weeks (P=0.003). Naive CD4 increases from baseline were associated with immune activation reductions (as declines from baseline of %CD8 cells expressing HLA-DR/CD38; P<0.0001), but these increases were attenuated in older patients, or in those with small thymuses. A 15% reduction in activation was associated with naive gains of 29.9 and 6.2 cells/μl in younger, versus older patients, or with gains of 25.7, 23.4, and 2.1 cells/μl in patients with the largest, intermediate, and smallest thymuses, respectively (P<0.01 for interactions between activation reduction and age-group or thymic volume). Older patients had significant B-cell expansion, higher levels of immune activation markers, and significantly attenuated naive CD4 cell gains associated with activation reduction.

Effects of HCV on Basal and Tat-Induced HIV LTR Activation

Hepatitis C virus (HCV) co-infection occurs in ∼30–40% of the HIV-infected population in the US. While a significant body of research suggests an adverse effect of HIV on HCV replication and disease progression, the impact of HCV on HIV infection has not been well studied. Increasing data suggest that hepatocytes and other liver cell populations can serve as reservoirs for HIV replication. Therefore, to gain insight into the impact of HCV on HIV, the effects of the HCV Core protein and infectious hepatitis C virions were evaluated on basal and Tat-induced activation of the HIV long terminal repeat (LTR) in hepatocytes. The HIV LTR was highly induced by the HIV transactivator protein Tat in hepatocytes. Activation varied according to the number of NF-kB binding sites present in the LTRs from different HIV subtypes. Involvement of the NF-kB binding pathway in LTR activation was demonstrated using an NF-kB inhibitor and deletion of the NF-kB binding sites. TNFα, a pro-inflammatory cytokine that plays an important role in HIV pathogenesis, also induced LTR activity in hepatocytes. However, HIV LTR activity was suppressed in hepatocytes in the presence of HCV Core protein, and the suppressive effect persisted in the presence of TNFα. In contrast, infectious hepatitis C virions upregulated HIV LTR activation and gene transcription. Core-mediated suppression remained unaltered in the presence of HCV NS3/4A protein, suggesting the involvement of other viral/cellular factors. These findings have significant clinical implications as they imply that HCV could accelerate HIV disease progression in HIV/HCV co-infected patients. Such analyses are important to elucidate the mechanisms by which these viruses interact and could facilitate the development of more effective therapies to treat HIV/HCV co-infection.