Residual Viremia Is Preceding Viral Blips and Persistent Low-Level Viremia in Treated HIV-1 Patients

Background

It has been suggested that low-level viremia or blips in HIV-infected patients on antiretroviral treatment are related to assay variation and/or increased sensitivity of new commercial assays. The 50-copy cut-off for virologic failure is, therefore, under debate.

Methods

Treated patients with low-level viremia (persistent viral loads (VL) of 50–1000 copies/mL, group A, N = 16) or a blip (single detectable VL, group B, N = 77) were compared to a control group (consistently suppressed viremia since start therapy (<50 copies/mL), N = 79). Residual viremia (detectable viral RNA <50 copies/ml) in the year preceding the first VL above 50 copies/mL (T0) was determined using Roche Cobas-Amplicor v1.5 or CAP-CTM v2.0. Subsequent virologic failure (2 consecutive VLs>500 or 1 VL>1000 copies/mL that was not followed by a VL<50 copies/mL; median follow up 34 months) was assessed.

Results

Significantly more patients in groups A and B had residual viremia in the year preceding T0 compared to controls (50% and 19% vs 3% respectively; p<0.001). Residual viremia was associated with development of low-level viremia or blips (OR 10.9 (95% CI 2.9–40.6)). Subsequent virologic failure was seen more often in group A (3/16) and B (2/77) than in the control group (0/79).

Conclusion

Residual viremia is associated with development of blips and low-level viremia. Virologic failure occurred more often in patients with low-level viremia. These results suggest that low-level viremia results from viral production/replication rather than only assay variation.     

Analysis of Human Immunodeficiency Virus Type 1 Viremia and Provirus in Resting CD4+ T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) can reduce human immunodeficiency virus type 1 (HIV-1) viremia to clinically undetectable levels. Despite this dramatic reduction, some virus is present in the blood. In addition, a long-lived latent reservoir for HIV-1 exists in resting memory CD4⁺ T cells. This reservoir is believed to be a source of the residual viremia and is the focus of eradication efforts. Here, we use two measures of population structure—analysis of molecular variance and the Slatkin-Maddison test—to demonstrate that the residual viremia is genetically distinct from proviruses in resting CD4⁺ T cells but that proviruses in resting and activated CD4⁺ T cells belong to a single population. Residual viremia is genetically distinct from proviruses in activated CD4⁺ T cells, monocytes, and unfractionated peripheral blood mononuclear cells. The finding that some of the residual viremia in patients on HAART stems from an unidentified cellular source other than CD4⁺ T cells has implications for eradication efforts.Successful treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART) reduces free virus in the blood to levels undetectable by the most sensitive clinical assays (18, 36). However, HIV-1 persists as a latent provirus in resting, memory CD4⁺ T lymphocytes (6, 9, 12, 16, 48) and perhaps in other cell types (45, 52). The latent reservoir in resting CD4⁺ T cells represents a barrier to eradication because of its long half-life (15, 37, 40-42) and because specifically targeting and purging this reservoir is inherently difficult (8, 25, 27).In addition to the latent reservoir in resting CD4⁺ T cells, patients on HAART also have a low amount of free virus in the plasma, typically at levels below the limit of detection of current clinical assays (13, 19, 35, 37). Because free virus has a short half-life (20, 47), residual viremia is indicative of active virus production. The continued presence of free virus in the plasma of patients on HAART indicates either ongoing replication (10, 13, 17, 19), release of virus after reactivation of latently infected CD4⁺ T cells (22, 24, 31, 50), release from other cellular reservoirs (7, 45, 52), or some combination of these mechanisms. Finding the cellular source of residual viremia is important because it will identify the cells that are still capable of producing virus in patients on HAART, cells that must be targeted in any eradication effort.Detailed analysis of this residual viremia has been hindered by technical challenges involved in working with very low concentrations of virus (13, 19, 35). Recently, new insights into the nature of residual viremia have been obtained through intensive patient sampling and enhanced ultrasensitive sequencing methods (1). In a subset of patients, most of the residual viremia consisted of a small number of viral clones (1, 46) produced by a cell type severely underrepresented in the peripheral circulation (1). These unique viral clones, termed predominant plasma clones (PPCs), persist unchanged for extended periods of time (1). The persistence of PPCs indicates that in some patients there may be another major cellular source of residual viremia (1). However, PPCs were observed in a small group of patients who started HAART with very low CD4 counts, and it has been unclear whether the PPC phenomenon extends beyond this group of patients. More importantly, it has been unclear whether the residual viremia generally consists of distinct virus populations produced by different cell types.Since the HIV-1 infection in most patients is initially established by a single viral clone (23, 51), with subsequent diversification (29), the presence of genetically distinct populations of virus in a single individual can reflect entry of viruses into compartments where replication occurs with limited subsequent intercompartmental mixing (32). Sophisticated genetic tests can detect such population structure in a sample of viral sequences (4, 39, 49). Using two complementary tests of population structure (14, 43), we analyzed viral sequences from multiple sources within individual patients in order to determine whether a source other than circulating resting CD4⁺ T cells contributes to residual viremia and viral persistence. Our results have important clinical implications for understanding HIV-1 persistence and treatment failure and for improving eradication strategies, which are currently focusing only on the latent CD4⁺ T-cell reservoir.     

Contribution of Follicular Dendritic Cells to Persistent HIV Viremia

HIV-1 infections cannot be completely eradicated by drug therapy, as the virus persists in reservoirs. Low-level plasma viremia has been detected in patients treated for over 7 years, but the cellular compartments that support this low-level viremia have not been identified. The decay of HIV-1 during treatment appears to occur in four phases, with the 3rd and 4th phases occurring when the virus is below the limit of detection of conventional assays. Here, we focus on the 3rd phase of decay, which has been estimated to have a half-life of 39 months. We show that follicular dendritic cells (FDC), which have been identified as an HIV reservoir, can be the main source of the low-level viremia detected during the 3rd phase of decay and contribute to viremia at even longer times. Our calculations show that the kinetics of leakage of virus from FDC is consistent with three types of available clinical data.     

Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection

Background

Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART.

Methods

Patients with plasma HIV RNA<50 c/mL added sustained-release VPA (Depakote ER®) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA).

Results

In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA.

Conclusions

The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.     

PD-L1 Blockade Differentially Impacts Regulatory T Cells from HIV-Infected Individuals Depending on Plasma Viremia

Blocking the PD-1/PD-L1 pathway has emerged as a potential therapy to restore impaired immune responses in human immunodeficiency virus (HIV)-infected individuals. Most reports have studied the impact of the PD-L1 blockade on effector cells and neglected possible effects on regulatory T cells (Treg cells), which play an essential role in balancing immunopathology and antiviral effector responses. The aim of this study was to define the consequences of ex vivo PD-L1 blockade on Treg cells from HIV-infected individuals. We observed that HIV infection led to an increase in PD-1+ and PD-L1+ Treg cells. This upregulation correlated with disease progression and decreased under antiretroviral treatment. Treg cells from viremic individuals had a particularly high PD-1 expression and impaired proliferative capacity in comparison with Treg cells from individuals under antiretroviral treatment. PD-L1 blockade restored the proliferative capacity of Treg cells from viremic individuals but had no effect on its suppressive capacity. Moreover, it increased the viral production in cell cultures from viremic individuals. This increase in viral production correlated with an increase in Treg cell percentage and a reduction in the CD4/Treg and CD8/Treg cell ratios. In contrast to the effect of the PD-L1 blockade on Treg cells from viremic individuals, we did not observe a significant effect on the proliferative capacity of Treg cells from individuals in whom viremia was controlled (either spontaneously or by antiretroviral treatment). However, PD-L1 blockade resulted in an increased proliferative capacity of HIV-specific-CD8 T cells in all subjects. Taken together, our findings suggest that manipulating PD-L1 in vivo can be expected to influence the net gain of effector function depending on the subject’s plasma viremia.     

Different Plasma Markers of Inflammation Are Influenced by Immune Recovery and cART Composition or Intensification in Treated HIV Infected Individuals

Background

HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies.

Methods

Longitudinal plasma samples (0–48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis.

Results

At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040).

Conclusions

The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers.     

HIV Prevalence and Risks Associated with HIV Infection among Transgender Individuals in Cambodia

IntroductionRecognizing transgender individuals have a high risk of HIV acquisition, and to inform policies and programming, we conducted an HIV prevalence and risk behaviors survey among transgender individuals in Cambodia.MethodsCross-sectional survey using a respondent driven sampling method with self-administered audio-computer assisted interviews. HIV testing was performed prior to the questionnaire with results available immediately after. Eligible participants were ≥18 years, identified as male at birth and self-identified/expressed as a different gender, and reported having sex with at least one male partner in past year. From six major urban centers of Cambodia, 891 transgender individuals were recruited.ResultsThe majority of the 891 participants self-identified as third gender or female (94.5%), were young (median age 23, IQR [20–27]), had secondary education or higher (80.5%), not married (89.7%), and employed (90.2%). The majority had first sex before 18 years (66.8%), with a male (79.9%), 37.9% having been paid or paying for this first sex. The rate of HIV positivity among participants was found to be 4.15%. Consistent condom use with male and female partners was low with all partner types, but particularly low with male partners when paying for sex (20.3%). The majority of participants reported having experienced discrimination in their lifetime (54.8%) and 30.3% had been assaulted. Multivariate analysis revealed that older age (adjusted OR = 14.73 [4.20, 51.67] for age 35–44 and adjusted OR = 7.63 [2.55, 22.81] for age 30–34), only having a primary school education or no schooling at all (adjusted OR = 2.62 [1.18, 5.80], being a resident of Siem Reap (adjusted OR = 7.44 [2.37,23.29], receiving payment at first sex (adjusted OR = 2.26 [1.00, 5.11], having sex during/after using drugs (adjusted OR = 2.90 [1.09,7.73]), inconsistent condom use during last anal sex (adjusted OR = 3.84 [1.58, 9.33]), and reporting low self-esteem (adjusted OR = 3.25 [1.35,7.85]) were independently associated with HIV infection.ConclusionsThis study confirms transgender individuals as one of the highest-risk groups for HIV infection in Cambodia. It suggests the need for programmatic strategies that mitigate identified associated risks and facilitate access to HIV care for this population.     

Association of Residual Plasma Viremia and Intima-Media Thickness in Antiretroviral-Treated Patients with Controlled Human Immunodeficiency Virus Infection

Background

While residual plasma viremia is commonly observed in HIV-infected patients undergoing antiretroviral treatment (ART), little is known about its subclinical consequences.

Methods

This cross-sectional study included 47 male, never-smoking, non-diabetic patients with ≥4 years of ART and controlled HIV-replication (HIV-viral load, VL <20 copies/mL for ≥1 year). Residual HIV-VL was measured using an ultrasensitive assay (quantification limit: 1 copy/ml). Patients were categorized as having detectable (D; 1-20 copies/mL, n = 14) or undetectable (UD; <1 copies/mL, n = 33) HIV-VL. Linear regression was used to model the difference in total carotid intima-media thickness [c-IMT, measures averaged across common carotid artery (cca), bifurcation, and internal carotid artery] and cca-IMT alone across detection groups. Multivariable models were constructed for each endpoint in a forward-stepwise approach.

Results

No significant differences were observed between viremia groups with respect to median ART-duration (9.6 years, IQR = 6.8–10.9), nadir CD4+T-cell (208/mm³, IQR = 143–378), and CD4+T-cell count (555/mm³, IQR = 458–707). Median adjusted inflammatory markers tended to be higher in patients with D- than UD-viremia, with differences in IL-10 being significant (p = 0.03). After adjustment on age, systolic blood pressure, and insulin resistance, mean cca-IMT was significantly lower in patients with undetectable (0.668 mm±0.010) versus detectable viremia (0.727 mm±0.015, p = 0.002). Cca-IMT was also independently associated with age and insulin resistance. Mean adjusted total c-IMT was no different between viremia groups (p = 0.2), however there was large variability in bifurcation c-IMT measurements.

Conclusions

Higher cca-IMT was observed in patients with detectable, compared to undetectable, HIV-VL in never-smoking ART-controlled patients, suggesting that residual HIV viremia may be linked to atherosclerosis.     

HIV-1 Residual Viremia Correlates with Persistent T-Cell Activation in Poor Immunological Responders to Combination Antiretroviral Therapy

Background

The clinical significance and cellular sources of residual human immunodeficiency virus type 1 (HIV-1) production despite suppressive combination antiretroviral therapy (cART) remain unclear and the effect of low-level viremia on T-cell homeostasis is still debated.

Methodology/Principal Findings

We characterized the recently produced residual viruses in the plasma and short-lived blood monocytes of 23 patients with various immunological responses to sustained suppressive cART. We quantified the residual HIV-1 in the plasma below 50 copies/ml, and in the CD14^high CD16⁻ and CD16⁺ monocyte subsets sorted by flow cytometry, and predicted coreceptor usage by genotyping V3 env sequences.We detected residual viremia in the plasma of 8 of 10 patients with poor CD4⁺ T-cell reconstitution in response to cART and in only 5 of 13 patients with good CD4⁺ T-cell reconstitution. CXCR4-using viruses were frequent among the recently produced viruses in the plasma and in the main CD14^high CD16⁻ monocyte subset. Finally, the residual viremia was correlated with persistent CD4⁺ and CD8⁺ T-cell activation in patients with poor immune reconstitution.

Conclusions

Low-level viremia could result from the release of archived viruses from cellular reservoirs and/or from ongoing virus replication in some patients. The compartmentalization of the viruses between the plasma and the blood monocytes suggests at least two origins of residual virus production during effective cART. CXCR4-using viruses might be produced preferentially in patients on cART. Our results also suggest that low-level HIV-1 production in some patients may contribute to persistent immune dysfunction despite cART.     

Residual Disinfection of Wool Blankets Treated with Formaldehyde

SUMMARY: Treatment with formaldehyde during laundering conferred a persistent residual disinfectant action on wool blankets but not on cotton ones. The former was shown by a slower rate of bacterial contamination of blankets during use or by the more rapid disappearance of nonsporing bacteria from contaminated blankets during storage. The formaldehyde treated blankets had no perceptible odour during use, and did not cause irritation of the skin or mucous membranes. It is suggested that the formaldehyde treatment of wool blankets might be worthy of trial as a means of reducing bacterial contamination in rooms occupied by patients with a high risk of infection.     

Comprehensive Evaluation of the Immune Risk Phenotype in Successfully Treated HIV-Infected Individuals

BackgroundDespite successful treatment and CD4+ T-cell recovery, HIV-infected individuals often experience a profound immune dysregulation characterized by a persistently low CD4:CD8 T-cell ratio. This residual immune dysregulation is reminiscent of the Immune Risk Phenotype (IRP) previously associated with morbidity and mortality in the uninfected elderly (>85 years). The IRP consists of laboratory markers that include: a low CD4:CD8 T-cell ratio, an expansion of CD8+CD28- T-cells and cytomegalovirus (CMV) seropositivity. Despite the significant overlap in immunological phenotypes between normal aging and HIV infection, the IRP has never been evaluated in HIV-infected individuals. In this pilot study we characterized immune changes associated with the IRP in a sample of successfully treated HIV-infected subjects.Methods18 virologically suppressed HIV-infected subjects were categorized into 2 groups based on their IRP status; HIV+IRP+, (n = 8) and HIV+IRP-, (n = 10) and compared to 15 age-matched HIV uninfected IRP negative controls. All individuals were assessed for functional and phenotypic immune characteristics including: pro-inflammatory cytokine production, antigen-specific proliferation capacity, replicative senescence, T-cell differentiation and lymphocyte telomere length.ResultsCompared to HIV-infected subjects without an IRP, HIV+IRP+ subjects exhibited a higher frequency of TNF-α-producing CD8+ T-cells (p = 0.05) and a reduced proportion of CD8+ naïve T-cells (p = 0.007). The IRP status was also associated with a marked up-regulation of the replicative senescence markers CD57 and KLGR1, on the surface of CD8+T-cells (p = 0.004). Finally, HIV+IRP+ individuals had a significantly shorter mean lymphocyte telomere length than their non-IRP counterparts (p = 0.03).ConclusionsOur findings suggest that, despite similar levels of treatment-mediated viral suppression, the phenotypic and functional immune characteristics of HIV+IRP+ individuals are distinct from those observed in non-IRP individuals. The IRP appears to identify a subset of treated HIV-infected individuals with a higher degree of immune senescence.     

The Immunologic Effects of Mesalamine in Treated HIV-Infected Individuals with Incomplete CD4+ T Cell Recovery: A Randomized Crossover Trial

The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts <350 cells/mm³ and plasma HIV RNA levels <40 copies/ml on antiretroviral therapy (ART) to add mesalamine vs. placebo to their existing regimen for 12 weeks followed by a 12 week crossover to the other arm. Compared to placebo-treated subjects, mesalamine-treated subjects did not experience any significant change in the percent CD38+HLA-DR+ peripheral blood CD4+ and CD8+ T cells at week 12 (P  = 0.38 and P  = 0.63, respectively), or in the CD4+ T cell count at week 12 (P  = 0.83). The percent CD38+HLA-DR+ CD4+ and CD8+ T cells also did not change significantly in rectal tissue (P  = 0.86, P  = 0.84, respectively). During the period of mesalamine administration, plasma sCD14, IL-6, D-dimer, and kynurenine to tryptophan ratio were not changed significantly at week 12 and were similarly unchanged at week 24. This study suggests that, at least under the conditions studied, the persistent immune activation associated with HIV infection is not impacted by the anti-inflammatory effects of mesalamine.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01090102","term_id":"NCT01090102"}}NCT01090102     

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

Background

Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.

Methods and Findings

Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median −0.2 and −0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus −44 cells/mm³, p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.

Conclusion

In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00515827","term_id":"NCT00515827"}}NCT00515827 Please see later in the article for the Editors'' Summary     

HIV-DNA in the Genital Tract of Women on Long-Term Effective Therapy Is Associated to Residual Viremia and Previous AIDS-Defining Illnesses

Objectives

To assess the impact of long-term combined antiretroviral therapy (cART) on HIV-RNA and HIV-DNA levels in cervicovaginal secretions of HIV-1-infected women with sustained undetectable plasma RNA viral load (PVL); to explore factors predictive of residual viral shedding; and to evaluate the risk of heterosexual transmission.

Methods

Women with undetectable PVL (<50 copies/mL) for >6 months were included in this cross-sectional study. HIV-RNA and HIV-DNA were measured in blood and cervicovaginal lavage fluid (CVL). Women were systematically tested for genital infections. The risk of transmission to male partners during unprotected intercourse was estimated.

Results

Eighty-one women composed the study population: all had HIV-RNA <40 copies/mL in CVL. HIV-DNA was detectable in CVL of 29/78 patients (37%). There was a weak positive correlation between HIV-DNA levels in PBMCs and CVL (r = 0.20; p = 0.08). In multivariate analysis, two factors were associated with HIV-DNA detection in CVL: previous AIDS-defining illnesses (OR = 11; 95%CI = 2–61) and current residual viremia (20<PVL<50 cp/mL) (OR = 3.4; 95%CI = 1.1–10.9). Neither the classes of cART regimen nor the presence of genital bacterial or fungal colonization were associated with HIV-DNA detection in CVL. Twenty-eight percent of the women had unprotected intercourse with their regular HIV-seronegative male partner, for between 8 and 158 months. None of their male partners became infected, after a total of 14 000 exposures.

Conclusion

In our experience, HIV-RNA was undetectable in the genital tract of women with sustained control of PVL on cART. HIV-DNA shedding persisted in about one third of cases, with no substantial evidence of residual infectiousness.     

Higher CD27+CD8+ T Cells Percentages during Suppressive Antiretroviral Therapy Predict Greater Subsequent CD4+ T Cell Recovery in Treated HIV Infection

HIV-mediated immune dysfunction may influence CD4⁺ T cell recovery during suppressive antiretroviral therapy (ART). We analyzed cellular biomarkers of immunological inflammation, maturation, and senescence in HIV-infected subjects on early suppressive ART. We performed longitudinal analyses of peripheral immunological biomarkers of subjects on suppressive ART (n = 24) from early treatment (median 6.4 months, interquartile range [IQR] 4.8–13.9 months) to 1–2 years of follow-up (median 19.8 months, IQR 18.3–24.6 months). We performed multivariate regression to determine which biomarkers were associated with and/or predictive of CD4⁺ T cell recovery. After adjusting for the pre-ART CD4⁺ T cell count, age, proximal CD4⁺ T cell count, and length of ART medication, the percentage of CD27⁺CD8⁺ T cells remained significantly associated with the CD4⁺ T cell recovery rate (β = 0.092 cells/ul/month, P = 0.028). In HIV-infected subjects starting suppressive ART, patients with the highest percentage of CD8⁺ T cells expressing CD27 had the greatest rate of CD4⁺ T cell recovery.