Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
A major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the “reservoir”). We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART).
We evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS) assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR); integrated DNA (Alu PCR); unspliced RNA (rtPCR), multiply-spliced RNA (TILDA), residual plasma HIV RNA (single copy PCR), and replication-competent virus (outgrowth assay). We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR). Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables.
Among 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years), the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004) and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003). However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results.
Our findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment.
Disulfiram activates HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate diulfiram exposure.
We conducted a prospective dose escalation study in order to optimise disulfiram exposure. Thirty people with HIV on suppressive antiretroviral therapy (ART) were enrolled, allocated sequentially to one of three dosing cohorts and received disulfiram daily for three days at a dose of 500mg, 1000mg or 2000mg. The primary endpoint was cell-associated unspliced (CA-US) HIV RNA in CD4+ T-cells. The study is registered with ClinicalTrials.gov, number NCT01944371.
The estimated fold increases in CA-US HIV RNA during and post-disulfiram for each cohort were: 500mg: 1·7 (95% confidence interval 1·3 – 2·2) and 2·1 (1·5 – 2·9); 1000mg: 1·9 (1·6 – 2·4) and 2·5 (1·9 – 3·3); and 2000mg: 1·6 (1·2 – 2·1) and 2·1 (1·5 – 3·1) respectively (p<0·003 for all). Disulfiram was well tolerated at all doses.
Short-term administration of disulfiram resulted in increases in CA-US HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV.
Abnormally high levels of T-cell activation can persist in HIV-infected subjects despite effective anti-retroviral therapy (ART) and has been associated with negative health outcomes. The nature of the antigenic drivers or other causes of this residual T-cell activation remain uncertain. Anelloviruses are universally acquired soon after birth, resulting in persistent viremia, and considered part of the commensal human virome. Reduced immunocompetence results in increased anellovirus levels.
To test whether increased levels of anelloviruses or other viruses in plasma are associated with higher levels of persistent T-cell activation during ART.
Two amplification methods combined with next generation sequencing were used to detect all viruses and estimate relative anellovirus levels in plasma from 19 adults on effective ART who exhibited a wide range of T-cell activation levels.
Nucleic acids from HBV and HCV were detected in one patient each while pegivirus A (GBV-C) was found in three patients. Anellovirus DNA was detected in all patients with some individuals carrying up to eight different genotypes. Specific anellovirus genotypes or higher level of co-infections were not detected in subjects with higher levels of T-cell activation. No association was detected between relative plasma anellovirus DNA levels and the percentage of activated CD4 or CD8 T cells.
Human anelloviruses were detected in all HIV suppressed subjects, exhibited a wide range of viremia levels, and were genetically highly diverse. The level of persistent T-cell activation was not correlated with the level of viremia or genotypes present indicating that anellovirus antigens are unlikely to be a dominant source of antigens driving chronic T-cell activation.
Anellovirus; Torque teno virus; Virome; HLA-DR+CD38+; T-cell activation; HIV
In chronic human immunodeficiency virus (HIV)-1 infection, long-lived latently infected cells are the major barrier to virus eradication and functional cure. Several therapeutic strategies to perturb, eliminate, and/or control this reservoir are now being pursued in the clinic. These strategies include latency reversal agents (LRAs) designed to reactivate HIV-1 ribonucleic acid transcription and virus production and a variety of immune-modifying drugs designed to reverse latency, block homeostatic proliferation, and replenish the viral reservoir, eliminate virus-producing cells, and/or control HIV replication after cessation of antiretroviral therapy. This review provides a summary of ongoing clinical trials of HIV LRAs and immunomodulatory molecules, and it highlights challenges in the comparison and interpretation of the expected trial results.
anti-HIV agents; clinical trial; HIV-1; latency-reversing agents; viral reservoir
Th17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown.
Here, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6+CCR4+ (Th17) and CCR6+CXCR3+ (Th1Th17) subsets, we reveal the existence of two novel CCR6+ subsets, lacking (double negative, CCR6+DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6+DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6+DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6+DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6+DN cells were the most predominant CCR6+ subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6+DN of ART-treated individuals.
Together, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6+CD4+ T-cells and support the major contribution of CCR6+DN cells to HIV persistence during ART.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-016-0293-6) contains supplementary material, which is available to authorized users.
Human; Th17; CCR6; CCR4; CXCR3; HIV reservoirs; ART
The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART).
Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4+ T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologic suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7–9 months.
DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens.
Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.
HIV-1 persistence; HIV-1 reservoir; memory T cells
Little is known about the humoral immune response against DNA prime-recombinant adenovirus 5 (rAd5) boost HIV vaccine among HIV-infected patients on long-term suppressive antiretroviral therapy (ART). Previous studies emphasized cellular immune responses; however, current research suggests both cellular and humoral responses are likely required for a successful therapeutic vaccine. Thus, we aimed to understand antibody response and function induced by vaccination of ART-treated HIV-1-infected patients with immune recovery. All subjects participated in EraMune 02, an open-label randomized clinical trial of ART intensification followed by a six plasmid DNA prime (envA, envB, envC, gagB, polB, nefB) and rAd5 boost HIV vaccine with matching inserts. Antibody binding levels were determined with a recently developed microarray approach. We also analyzed neutralization efficiency and antibody-dependent cellular cytotoxicity (ADCC). We found that the DNA prime-rAd5 boost vaccine induced a significant cross-clade HIV-specific antibody response, which correlated with antibody neutralization efficiency. However, despite the increase in antibody binding levels, the vaccine did not significantly stimulate neutralization or ADCC responses. This finding was also reflected by a lack of change in total CD4+ cell associated HIV DNA in those who received the vaccine. Our results have important implications for further therapeutic vaccine design and administration, especially in HIV-1 infected patients, as boosting of preexisting antibody responses are unlikely to lead to clearance of latent proviruses in the HIV reservoir.
HIV; Acute; Reservoir; Early treatment; Viral set-point; Cell-associated HIV DNA
We sought to determine whether biomarkers ST2, GDF-15, NT-proBNP, and high-sensitivity Troponin I are elevated in HIV-infected patients and associated with cardiovascular dysfunction and all-cause mortality.
HIV-infected individuals have high rates of cardiovascular disease. Markers of myocardial stress may identify at-risk patients and provide additional prognostic information.
Biomarkers and echocardiograms were assessed in 332 HIV-infected patients and 50 age- and gender-matched controls. Left ventricular systolic dysfunction (LVSD) was defined as ejection fraction <50%, diastolic dysfunction (DD) as ≥stage 1, and pulmonary hypertension as PASP ≥35mmHg. Mortality data was obtained from the National Death Index.
HIV patients were a median 49 years and 80% male. Compared with controls, HIV patients had higher percent estimates of all biomarkers except ST2 and interleukin-6. Among HIV patients, 45% had DD; only ST2 was associated with DD (RR 1.36, p=0.047). LVSD was rare in this cohort (5%). Pulmonary hypertension was present in 27% of HIV patients and associated with GDF-15 (RR 1.18, p=0.04), NT-proBNP (RR 1.18, p=0.007), and Cystatin C (RR 1.54, p=0.03). Thirty-eight deaths occurred among HIV subjects over a median 6.1 years. In adjusted analysis, all-cause mortality was independently predicted by ST2 (HR 2.04, p=0.010), GDF-15 (HR 1.42, p=0.0054), hsCRP (HR 1.25, p=0.023) and D-dimer (HR 1.49, p=0.029). Relationships were unchanged when analyses were restricted to virally-suppressed HIV-infected patients on antiretroviral therapy.
Among HIV-infected individuals, ST2 and GDF-15 are associated with both cardiovascular dysfunction and all-cause mortality and may be useful at identifying those at-risk for developing cardiovascular events and death.
HIV; death; cardiovascular dysfunction; biomarkers; mortality
HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals.
The persistence of HIV in a small pool of long-lived latently infected resting CD4+ T cells is a major barrier to viral eradication. Identifying cellular markers that are preferentially expressed at the surface of latently infected cells may lead to novel therapeutic strategies to cure HIV infection. We identified PD-1, TIGIT and LAG-3 as markers preferentially expressed at the surface of infected cells in individuals receiving ART. CD4+ T cells co-expressing these markers were highly enriched for cells carrying HIV. Our results suggest that PD-1, TIGIT and LAG-3 may represent new molecular targets to interfere with HIV persistence during ART.
Purpose of review
The present review will highlight some of the recent findings regarding the capacity of HIV-1 to replicate during antiretroviral therapy (ART).
Although ART is highly effective at inhibiting HIV replication, it is not curative. Several mechanisms contribute to HIV persistence during ART, including HIV latency, immune dysfunction, and perhaps persistent low-level spread of the virus to uninfected cells (replication). The success in curing HIV will depend on efficiently targeting these three aspects. The degree to which HIV replicates during ART remains controversial. Most studies have failed to find any evidence of HIV evolution in blood, even with samples collected over many years, although a recent very intensive study of three individuals suggested that the virus population does shift, at least during the first few months of therapy. Stronger but still not definitive evidence for replication comes from a series of studies in which standard regimens were intensified with an integration inhibitor, resulting in changes in episomal DNA (blood) and cell-associated RNA (tissue). Limited drug penetration within tissues and the presence of immune sanctuaries have been argued as potential mechanisms allowing HIV to spread during ART. Mathematical models suggest that HIV replication and evolution is possible even without the selection of fully drug-resistant variants. As persistent HIV replication could have clinical consequences and might limit the efficacy of curative interventions, determining if HIV replicates during ART and why, should remain a key focus of the HIV research community.
Residual viral replication likely persists in lymphoid tissues, at least in a subset of individuals. Abnormal levels of immune activation might contribute to sustain virus replication.
abnormal levels of immune activation and inflammation; cell-to-cell infection; HIV residual replication during ART; limited drug penetration within tissues, presence of immune sanctuaries
Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies.
While antiretroviral therapy (ART) has significantly decreased the morbidity and mortality associated with HIV infection, a cure is not achieved due to the persistence of HIV latently-infected cells during treatment. Identifying the principal host immune determinants governing HIV transcription, latency, and infectivity in vivo will be a critical step in developing an effective curative strategy for HIV infection. In this study, we demonstrate that the human immunomodulatory carbohydrate-binding protein galectin-9 is a determinant of HIV latency in HIV-infected individuals on suppressive ART. Administration of galectin-9 potently reactivates latent HIV in CD4+ T cells ex vivo, by signaling through specific glycans on the cell surface to modulate the gene expression levels of key host factors that regulate HIV transcription. Furthermore, galectin-9 induces the host APOBEC3 proteins which lethally mutagenize the HIV genome, attenuating viral infectivity. Our findings reveal a novel biological function of human galectin-9, and demonstrate that host glycans on the surface of infected cells mediate signals that define the transcriptional state and infectivity of HIV. Our findings suggest that galectin-9 and the host glycosylation machinery may be exploited to eradicate the latent HIV reservoir.
Geriatric syndromes such as falls, frailty, and functional impairment are multifactorial conditions used to identify vulnerable older adults. Limited data exists on these conditions in older HIV-infected adults and no studies have comprehensively examined these conditions.
Geriatric syndromes including falls, urinary incontinence, functional impairment, frailty, sensory impairment, depression and cognitive impairment were measured in a cross-sectional study of HIV-infected adults age 50 and older who had an undetectable viral load on antiretroviral therapy (ART). We examined both HIV and non-HIV related predictors of geriatric syndromes including sociodemographics, number of co-morbidities and non-antiretroviral medications, and HIV specific variables in multivariate analyses.
We studied 155 participants with a median age of 57 (IQR 54-62); (94%) were men. Pre-frailty (56%), difficulty with instrumental activities of daily living (46%), and cognitive impairment (47%) were the most frequent geriatric syndromes. Lower CD4 nadir (IRR 1.16, 95% CI 1.06-1.26), non-white race (IRR 1.38, 95% CI 1.10-1.74), and increasing number of comorbidities (IRR 1.09, 95%CI 1.03-1.15) were associated with increased risk of having more geriatric syndromes.
Geriatric syndromes are common in older HIV infected adults. Treatment of comorbidities and early initiation of ART may help to prevent development of these age related complications. Clinical care of older HIV-infected adults should consider incorporation of geriatric principles.
Aging; Frailty; Function
Supplemental Digital Content is Available in the Text.
HIV infection and biomarkers of inflammation [measured by interleukin-6 (IL-6)], monocyte activation [soluble CD14 (sCD14)], and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of comorbid diseases.
Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC), we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14, and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or July 25, 2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression.
During 6.9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14, or D-dimer were 2–3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared with uninfected people [incidence rate ratio (95% CI): 1.31 (1.06 to 1.62)]. Mortality risk increased with increasing quartiles of IL-6, sCD14, and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14, and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA ≥10,000 copies per milliliter) compared with uninfected people—hazard ratio (95% CI) decreased from 2.18 (1.60 to 2.99) to 2.00 (1.45 to 2.76).
HIV infection is associated with elevated IL-6, sCD14, and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.
HIV; mortality; inflammation; monocyte activation; coagulation
Supplemental Digital Content is Available in the Text.
To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART).
Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems.
Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9–12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes.
In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9–12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were −5.3 (−18.6 to 7.9) and −31.7 (−52.0 to −11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies.
Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.
HIV; CD4 cell count; HIV RNA; monitoring; observational studies; mortality
To determine viral and immune factors involved in transmission and control of HIV-1 infection in persons without functional CCR5
Understanding transmission and control of HIV-1 in persons homozygous for CCR5Δ32 is important given efforts to develop HIV-1 curative therapies aimed at modifying or disrupting CCR5 expression.
We identified two HIV-infected CCR5Δ32/Δ32 individuals among a cohort of patients with spontaneous control of HIV-1 infection without antiretroviral therapy and determined co-receptor usage of the infecting viruses. We assessed genetic evolution of full-length HIV-1 envelope sequences by single-genome analysis from one participant and his sexual partner, and explored HIV-1 immune responses and HIV-1 mutations following virologic escape and disease progression.
Both participants experienced viremia of less than 4,000 RNA copies/ml with preserved CD4+ T cell counts off ART for at least 3.3 and 4.6 years after diagnosis, respectively. One participant had phenotypic evidence of X4 virus, had no known favorable HLA alleles, and appeared to be infected by minority X4 virus from a pool that predominately used CCR5 for entry. The second participant had virus that was unable to use CXCR4 for entry in phenotypic assay but was able to engage alternative viral coreceptors (e.g. CXCR6) in vitro.
Our study demonstrates that individuals may be infected by minority X4 viruses from a population that predominately uses CCR5 for entry, and that viruses may bypass traditional HIV-1 coreceptors (CCR5 and CXCR4) completely by engaging alternative coreceptors to establish and propagate HIV-1 infection.
HIV-1; CCR5; CCR5 Δ32 mutation; HIV tropism; HIV controller; viral coreceptor
Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts.
In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower “usual” levels of IL-6 and D-dimer.
Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower “usual” IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal.
Both IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.
A small subset of HIV-positive adults have low HIV RNA in the absence of therapy, sometimes for years. Clinical factors associated with low HIV RNA in early infection have not been well defined.
We assessed factors associated with low plasma HIV RNA level at study entry in the Strategic Timing of AntiRetroviral Treatment (START) trial. All START participants had a baseline HIV RNA assessment within 60 days prior to randomisation. The key covariables considered for this analysis were race, hepatitis B virus (HBV) and hepatitis C virus (HCV) status. We assessed factors associated with HIV RNA ≤50 and ≤400 copies/mL using logistic regression. Because of the strong association between region of randomisation and baseline low HIV RNA, analyses were stratified by region.
We found that of 4676 eligible participants randomised in START with a baseline HIV RNA assessment, 113 (2.4%) had HIV RNA ≤50 copies/mL at baseline, and a further 257 (5.5%) between 51 and 400 copies/mL. We found that HIV exposure routes other than male homosexual contact, higher HDL levels, higher CD4 cell counts, and higher CD4:CD8 ratio were associated with increased odds of low HIV RNA. HCV antibody positivity was borderline statistically significantly associated with low HIV RNA. Race and HBV surface antigen positivity were not significantly associated with low HIV RNA.
In a modern cohort of early untreated HIV infection we found that HIV exposure routes other than male homosexual contact and higher HDL were associated with increased odds of low HIV RNA.
HIV; antiretroviral therapy; viral load
Human immunodeficiency virus (HIV) replication causes lymphoid tissue (LT) fibrosis, which causes CD4+ T-cell depletion. It is unknown whether people who spontaneously control HIV replication have LT fibrosis. We measured LT fibrosis and CD4+ T cells in 25 HIV controllers, 10 noncontrollers, 45 HIV-positive individuals receiving therapy, and 10 HIV-negative individuals. Controllers had significant LT fibrosis and CD4+ T-cell depletion, similar to noncontrollers, but the so-called Berlin patient (in whom HIV infection was cured) had near normal LT. Thus, LT fibrosis occurs in all HIV-infected subjects, and current therapy does not reverse it. Reversal of fibrosis during a curative intervention suggests that ongoing low-level virus production may maintain LT fibrosis.
HIV; fibrosis; HIV controllers
Background. It is unknown what properties would be required to make an intervention in low income countries that can eradicate or control human immunodeficiency virus (HIV) without antiretroviral therapy (ART) cost-effective.
Methods. We used a model of HIV and ART to investigate the effect of introducing an ART-free viral suppression intervention in 2022 using Zimbabwe as an example country. We assumed that the intervention (cost: $500) would be accessible for 90% of the population, be given to those receiving effective ART, have sufficient efficacy to allow ART interruption in 95%, with a rate of viral rebound of 5% per year in the first 3 months, and a 50% decline in rate with each successive year.
Results. An ART-free viral suppression intervention with these properties would result in >0.53 million disability-adjusted-life-years averted over 2022–2042, with a reduction in HIV program costs of $300 million (8.7% saving). An intervention of this efficacy costing anything up to $1400 is likely to be cost-effective in this setting.
Conclusions. Interventions aimed at curing HIV infection have the potential to improve overall disease burden and to reduce costs. Given the effectiveness and cost of ART, such interventions would have to be inexpensive and highly effective.
HIV; cure; economic evaluation; model; antiretroviral therapy
Human immunodeficiency virus-infected individuals have benefited from improved viral suppression, but a discrepancy in end-stage renal disease risk between black and nonblack HIV-infected persons remains, in part due to continued disparities in antiretroviral use and viral suppression, and higher rates of comorbidities.
Background. Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks.
Methods. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18–80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD.
Results. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8–3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9–5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection.
Conclusions. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.
end-stage renal disease (ESRD); chronic kidney disease (CKD); HIV infection/AIDS; HIV/AIDS; glomerular filtration rate (GFR)
The eradication of HIV necessitates elimination of the HIV latent reservoir. Identifying host determinants governing latency and reservoir size in the setting of antiretroviral therapy (ART) is an important step in developing strategies to cure HIV infection. We sought to determine the impact of cell-intrinsic immunity on the HIV latent reservoir.
We investigated the relevance of a comprehensive panel of established anti-HIV-1 host restriction factors to multiple established virologic and immunologic measures of viral persistence in HIV-1-infected, ART-suppressed individuals.
We measured the mRNA expression of 42 anti-HIV-1 host restriction factors, levels of cell-associated HIV-1 RNA, levels of total pol and 2-LTR circle HIV-1 DNA, and immunophenotypes of CD4+ T cells in 72 HIV-1-infected subjects on suppressive ART (23 subjects initiated ART <1 year post-infection, and 49 subjects initiated ART >1 year post-infection). Correlations were analyzed using non-parametric tests.
The enhanced expression of a few select host restriction factors, p21, schlafen 11, and PAF1, was strongly associated with reduced CD4+ T cell-associated HIV RNA during ART (p<0.001). In addition, our data suggested that ART perturbs the regulatory relationship between CD4+ T cell activation and restriction factor expression. Lastly, cell-intrinsic immune responses were significantly enhanced in subjects who initiated ART during early versus chronic infection, and may contribute to the reduced reservoir size observed in these individuals.
Intrinsic immune responses modulate HIV persistence during suppressive ART, and may be manipulated to enhance the efficacy of ART and promote viral eradication through reversal of latency in vivo.
HIV latency; antiretroviral therapy; intrinsic immunity; host restriction factors; p21; schlafen 11; PAF1 complex
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression