• HIV/AIDS
• bioinformatics
• infectious disease dynamics

• Humans
• HIV-1/genetics
• HIV Infections/genetics
• HIV Infections/virology
• HIV Infections/immunology
• HIV Infections/transmission
• CD4-Positive T-Lymphocytes/virology
• CD4 Lymphocyte Count
• Viral Load

• European Research Council
• Medical Research Council

• BCG
• HIV
• M. tuberculosis
• Vaccine
• immunosenescence

• R15 HL143545 NHLBI NIH HHS

• Brazil
• Disparities
• HIV care continuum
• Key and vulnerable populations
• Life expectancy
• Modeling

• Humans
• Male
• Female
• Adolescent
• Homosexuality, Male
• Brazil/epidemiology
• Sexual and Gender Minorities
• Transgender Persons
• Sexual Behavior
• HIV Infections/epidemiology

• R37 AI058736 NIAID NIH HHS
• UM1 AI069476 NIAID NIH HHS

• HIV-1
• disease progression
• per-pathogen pathogenicity
• set-point viral load
• subtypes
• virulence

• Diffusion tensor imaging
• HIV-associated neurocognitive disorders
• Nadir CD4
• White matter

• HIV
• MACS/WIHS Combined Cohort Study
• Multicenter AIDS Cohort Study
• Women’s Interagency HIV Study
• biorepositories
• cohort studies
• collaborative research
• comorbidity

• Acquired Immunodeficiency Syndrome/drug therapy
• Acquired Immunodeficiency Syndrome/epidemiology
• Adult
• Aged
• Aged, 80 and over
• Aging/physiology
• Anti-Retroviral Agents/therapeutic use
• CD4 Lymphocyte Count
• Cohort Studies
• Comorbidity
• Female
• HIV Infections/drug therapy
• HIV Infections/epidemiology
• HIV Infections/ethnology
• Humans
• Longitudinal Studies
• Male
• Middle Aged
• Racial Groups
• Research Design
• Residence Characteristics
• Risk Factors
• Socioeconomic Factors
• United States
• Viral Load

• U01 HL146205 NHLBI NIH HHS
• P30 AI051519 NIAID NIH HHS
• U01 HL146208 NHLBI NIH HHS
• U01 HL146192 NHLBI NIH HHS
• U01 HL146242 NHLBI NIH HHS
• U01 HL146201 NHLBI NIH HHS
• U01 HL146193 NHLBI NIH HHS
• P30 AI027763 NIAID NIH HHS
• U01 AI035040 NIAID NIH HHS
• U01 HL146194 NHLBI NIH HHS
• U01 HL146241 NHLBI NIH HHS
• P30 AI027767 NIAID NIH HHS
• P30 AI050409 NIAID NIH HHS
• U01 HL146333 NHLBI NIH HHS
• R01 MD010680 NIMHD NIH HHS
• U01 HL146245 NHLBI NIH HHS
• U01 HL146204 NHLBI NIH HHS
• U01 HL146202 NHLBI NIH HHS
• UL1 TR000004 NCATS NIH HHS
• U01 HL146240 NHLBI NIH HHS
• U01 HL146203 NHLBI NIH HHS
• P30 AI050410 NIAID NIH HHS
• National Institutes of Health

The widely-expressed molecule CD38 is a single-stranded type II transmembrane glycoprotein that is mainly involved in regulating the differentiation and activation state of the cell. CD38 has broad and complex functions, including enzymatic activity, intercellular signal transduction, cell activation, cytokine production, receptor function and adhesion activity, and it plays an important role in the physiological and pathological processes of many diseases. Many studies have shown that CD38 is related to the occurrence and development of HIV infection, and CD38 may regulate its progression through different mechanisms. Therefore, investigating the role of CD38 in HIV infection and the potential signaling pathways that are involved may provide a new perspective on potential treatments for HIV infection. In the present review, the current understanding of the roles CD38 plays in HIV infection are summarized. In addition, the specific role of CD38 in the process of HIV infection of human CD4⁺ T lymphocytes is also discussed.

• ART
• Abnormal immune activation
• CD38 molecule
• HIV

• Anti-Retroviral Agents/economics
• Anti-Retroviral Agents/therapeutic use
• Continuity of Patient Care
• Cost-Benefit Analysis
• HIV Infections/drug therapy
• HIV Infections/mortality
• HIV Infections/transmission
• Humans
• Models, Theoretical
• Mortality
• United States
• United States Health Resources and Services Administration

• CCR5
• CXCR4
• HIV-1
• R5X4sig
• chemokine
• cofilin
• gp120
• signaling.

The time to the onset of AIDS symptoms in an HIV infected individual is known to correlate inversely with viremia and the level of immune activation. The correlation exists against the background of strong individual fluctuations demonstrating the existence of hidden variables depending on patient and virus parameters. At the moment, prognosis of the time to AIDS based on patient parameters is not possible. In addition, it is of paramount importance to understand the reason of progression to AIDS in untreated patients to be able to learn to control it by means other than anti-retroviral therapy. Here we develop a mechanistic mathematical model to predict the speed of progression to AIDS in individual untreated patients and patients treated with suboptimal therapy, based on a single-time measurement of several virological and immunological parameters. We show that the gradual increase in virus fitness during a chronic infection causes slow gradual depletion of CD4 T cells. Using the existing evolution models of HIV, we obtain general expressions predicting the time to the onset of AIDS symptoms in terms of the patient parameters, for low-viremia and high-viremia patients separately. We show that the evolution model of AIDS fits the existing data on virus-time correlations better than the alternative model of the deregulation of homeostatic response.

• homeostasis
• host-virus interaction
• mathematical model
• progression to AIDS
• virus adaptation

• antiretroviral agents
• drug resistance
• human immunodeficiency virus
• microbial cultures
• virulence

To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults.

In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm³ and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm³ or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015.

We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm³ and VL was 4.04 (3.5–4.5) log₁₀ copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm³/year in the valaciclovir arm versus 58 cells/mm³/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (−1.2%/year versus −1.7%/year, P = 0.34). VL was 0.27 log₁₀ copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events.

Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.

• HIV
• REG3α
• gut damage
• inflammation
• microbial translocation

• Adult
• Anti-HIV Agents/therapeutic use
• Bacterial Translocation
• Biomarkers/blood
• CD4-CD8 Ratio
• Cross-Sectional Studies
• Disease Progression
• Fatty Acid-Binding Proteins/blood
• Female
• HIV Infections/blood
• HIV Infections/drug therapy
• HIV Infections/immunology
• HIV-1
• Humans
• Interleukin-6/blood
• Interleukin-8/blood
• Interleukins/blood
• Intestinal Mucosa/pathology
• Lipopolysaccharide Receptors/blood
• Lipopolysaccharides/blood
• Male
• Middle Aged
• Pancreatitis-Associated Proteins/blood
• Tumor Necrosis Factor-alpha/blood
• Viral Load
• beta-Glucans/blood
• Interleukin-22

• MOP 103230 CIHR
• 154051 CIHR
• PJT 166049 CIHR
• HIG133050 CIHR
• HB2-164064 CIHR
• MOP93770 CIHR
• TCO-125276 CIHR
• HAL-157985 CIHR

Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines.

• Disease progression
• Dual-infection
• Functional cure
• HIV-1
• HIV-2
• West Africa

Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.

This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.

HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.

Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.

LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

• CD38
• HIV LTNP
• HIV non-progression
• HLADR
• T-cell activation in HIV LTNP
• antiviral cytokine response in HIV LTNP.

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as “per-parasite pathogenicity”. Using viral load and CD4+ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence—measured as the rate of decline of CD4+ T cells—and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor–recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T-cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T-cell decline is 17% (5–30%), and that of the per-parasite pathogenicity is 17% (4–29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12–46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

• HIV
• disease tolerance
• evolution of virulence
• heritability
• per-parasite pathogenicity

• CD38
• CD4-Positive T lymphocytes
• HIV/AIDS
• NAD
• Warburg effect
• immune activation
• immunometabolism

• ADP-ribosyl Cyclase 1/genetics
• ADP-ribosyl Cyclase 1/metabolism
• Disease Progression
• Gene Expression Regulation
• HIV Infections/enzymology
• HIV Infections/genetics
• Humans
• Membrane Glycoproteins/genetics
• Membrane Glycoproteins/metabolism
• Up-Regulation

• R01 AI091526 NIAID NIH HHS
• R01 AI128864 NIAID NIH HHS
• AI091526 NIH HHS
• AI128864 NIH HHS

• criminal law
• criminalization
• human rights
• law and policy
• policy
• prosecution
• risk factors

• Consensus
• Criminal Law
• Disease Transmission, Infectious/legislation & jurisprudence
• Female
• HIV Infections/transmission
• Humans
• Male
• Phylogeny
• Sexual Behavior
• Viral Load

• UM1 AI069476 NIAID NIH HHS

Current Indian guidelines recommend twice-annual CD4 testing to monitor first-line antiretroviral therapy (ART), with a plasma HIV RNA test to confirm failure if CD4 declines, which would prompt a switch to second-line ART. We used a mathematical model to assess the clinical benefits and cost-effectiveness of alternative laboratory monitoring strategies in India. We simulated a cohort of HIV-infected patients initiating first-line ART and compared 11 strategies with combinations of CD4 and HIV RNA testing at varying frequencies. We included adaptive strategies that reduce the frequency of tests after 1 year from 6 to 12 months for virologically suppressed patients. We projected life expectancy, time on failed first-line ART, cumulative 10-year HIV transmissions, lifetime cost (2014 US dollars), and incremental cost-effectiveness ratios (ICERs). We defined strategies as cost-effective if their ICER was <1 × the Indian per capita gross domestic product (GDP, $1,600). We found that the current Indian guidelines resulted in a per person life expectancy (from mean age 37) of 150.2 months and a per person cost of $2,680. Adding annual HIV RNA testing increased survival by ∼8 months; adaptive strategies were less expensive than similar nonadaptive strategies with similar life expectancy. The most effective strategy with an ICER <1 × GDP was the adaptive HIV RNA strategy (ICER $840/year). Cumulative 10-year transmissions decreased from 27.2/1,000 person-years with standard-of-care to 20.9/1,000 person-years with adaptive HIV RNA testing. In India, routine HIV RNA monitoring of patients on first-line ART would increase life expectancy, decrease transmissions, be cost-effective, and should be implemented.

• HIV
• India
• cost-effectiveness
• laboratory monitoring

Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4⁺ T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell responses seem to be one of the main causes of HIV-1 control in elite controllers, we studied whether HIV-1 Gag-specific cytotoxic T lymphocyte (CTL) responses could also modulate disease control in VNPs. We characterized the immune responses from four VNPs compared to those of five standard progressors (SPs) during the first years of HIV-1 infection. We observed no differences in the breadth and frequency of Gag-specific cellular responses. Furthermore, we obtained 217 HIV-1^Gag clonal sequences in which the viral variability of Gag increased over 3 years of infection for synonymous and nonsynonymous mutations in both VNPs and SPs. VNPs evolution rates in gag were comparable to SPs. This observation is in line with a similar accumulation of CTL putative escape mutations in Gag epitopes targeted by CTL responses. Altogether, the absence of viral pathogenesis in VNP individuals seems to be independent of HIV-Gag-specific CTL responses. This novel information guides to the study of alternative mechanism of HIV-1 pathogenesis control.

IMPORTANCE Control of HIV infection has been widely studied in elite controllers or long-term nonprogressor models. However, there is a less-known group of individuals, termed viremic nonprogressors (VNPs), who maintain stable CD4⁺ T cell counts despite high plasma viremia. The mechanisms involved in this remarkable control of HIV-1 pathogenesis clearly have implications for the development of new drugs and vaccines. We show here for the first time that VNPs have immune responses and HIV-gag evolution similar to those of standard progressors. Remarkably, we demonstrate that the mechanism of pathogenesis control in these individuals differs from some elite controllers that are reported to have improved immune control. This is noteworthy since it opens the door to new, as-yet-unknown mechanisms for HIV control. Our novel results advance the understanding of mechanisms involved in viremic nonprogression and suggest that there are alternative mechanisms to the adaptive immune responses for an effective control of viral pathogenesis.

• CTL response
• HIV-1
• progression
• viral pathogenesis
• viremic nonprogressors

Persistent immune activation is a striking consequence of HIV-1 infection and a driving force of CD4⁺ T cell depletion and AIDS events during chronic infection. High level of T cell immune activation associates with antiretroviral therapy (ART)-treated clinical outcomes in chronically HIV-1-infected patients. However, the role of T cell activation during acute infection stage in subsequent CD4⁺ T cell decline in the absence of ART treatment is unknown. In this study, we enrolled 26 acutely HIV-1-infected patients in the absence of ART treatment from a prospective acute HIV-1 infection cohort in Beijing (PRIMO). A comprehensive analysis of CD4⁺ and CD8⁺ T cell immune activation during acute infection stage and the clinical outcomes was studied. We found that patients with higher level of CD4⁺ T cell activation (%CD38⁺HLA-DR⁺CD4⁺ T cells) exhibited more effective function (%IL-2 production and %ki67 expression) in CD4⁺ T cells compared to those from patients without increased T cell activation at the acute phase. Direct correlations were observed between CD4⁺ T cell activation and the percentages of IL-2-producing or ki67-expressing CD4⁺ T cells in patients at the acute phase of infection. Importantly, the increased levels of CD4⁺ T cell immune activation, IL-2 production, and cycling expression during acute infection were associated with less decline of CD4⁺ T cell after 2 years of infection. However, immune exhaustion molecules in acute infection, including CD160, T cell immunoglobulin and ITIM domain, programmed cell death protein 1, and T cell immunoglobulin and mucin 3, were not associated with the CD4⁺ T cell depletion. These significant associations of CD4⁺ T cell activation were not demonstrable for CD8⁺ T cell activation at the acute phase. Taken together, our observations provide new insight into the possible role of T cell activation in preventing CD4⁺ T cell depletion during acute HIV-1 infection.

• CD4+ T cell
• T cell immune activation
• T cell preservation
• acute HIV-1 infection
• immune exhaustion molecules

• HIV
• agent-based model
• calibration
• g-formula

• Adult
• Cause of Death/trends
• Female
• HIV Infections/metabolism
• HIV Infections/mortality
• Health Promotion
• Humans
• Male
• Middle Aged
• Models, Theoretical
• Mortality/trends
• Observation
• Population Health

• R01 AI042006 NIAID NIH HHS
• K01 DA042687 NIDA NIH HHS
• K01 HL123349 NHLBI NIH HHS
• R01 GM116525 NIGMS NIH HHS
• P30 AI060354 NIAID NIH HHS
• R01 AI073127 NIAID NIH HHS

• Early HIV infection
• Geenius assay
• HIV diagnosis
• Western Blot
• acute HIV infection

• AIDS Serodiagnosis/instrumentation
• AIDS Serodiagnosis/methods
• Adult
• Blotting, Western/instrumentation
• Blotting, Western/methods
• HIV Antibodies/blood
• HIV Infections/diagnosis
• HIV Infections/immunology
• HIV Infections/virology
• HIV-1/immunology
• HIV-2/immunology
• Humans
• Immunoassay/instrumentation
• Immunoassay/methods
• Male
• Middle Aged
• Sensitivity and Specificity

• Adult
• Aged
• Cohort Studies
• Europe
• Evolution, Molecular
• Female
• Genetic Variation
• Genome, Viral
• Genome-Wide Association Study
• HIV Infections/blood
• HIV Infections/microbiology
• HIV Seropositivity/blood
• HIV Seropositivity/microbiology
• HIV-1/genetics
• HIV-1/growth & development
• HIV-1/isolation & purification
• HIV-1/pathogenicity
• Human Immunodeficiency Virus Proteins/blood
• Human Immunodeficiency Virus Proteins/genetics
• Human Immunodeficiency Virus Proteins/metabolism
• Humans
• Male
• Middle Aged
• Models, Genetic
• Phylogeny
• Registries
• Seroconversion
• Viral Load
• Virulence

• K01 AI125086 NIAID NIH HHS
• MR/L01632X/1 Medical Research Council

The hall mark of human immunodeficiency virus (HIV) infection is a gradual loss of CD4+ T-cells and imbalance in CD4+ T-cell homeostasis, with progressive impairment of immunity that leads ultimately to death. HIV infection in humans is caused by two related yet distinct viruses: HIV-1 and HIV-2. HIV-2 is typically less virulent than HIV-1 and permits the host to mount a more effective and sustained T-cell immunity. Although both infections manifest the same clinical spectrum, the much lower rate of CD4+ T-cell decline and slower progression of disease in HIV-2 infected individuals have grabbed the attention of several researchers. Here, we review the most recent findings on the differential rate of decline of CD4+ T-cell in HIV-1 and HIV-2 infections and provide plausible reasons for the observed differences between the two groups.

• CD4+ T-cell
• HIV-1
• HIV-2
• immune activation
• pyroptosis

Abacavir and rilpivirine are alternative antiretroviral drugs for treatment-naïve HIV-infected patients. However, both drugs are only recommended for the patients who have pre-treatment HIV RNA <100,000 copies/mL. In resource-limited settings, pre-treatment HIV RNA is not routinely performed and not widely available. The aims of this study are to determine factors associated with pre-treatment HIV RNA <100,000 copies/mL and to construct a model to predict this outcome.

HIV-infected adults enrolled in the TREAT Asia HIV Observational Database were eligible if they had an HIV RNA measurement documented at the time of ART initiation. The dataset was randomly split into a derivation data set (75% of patients) and a validation data set (25%). Factors associated with pre-treatment HIV RNA <100,000 copies/mL were evaluated by logistic regression adjusted for study site. A prediction model and prediction scores were created.

A total of 2592 patients were enrolled for the analysis. Median [interquartile range (IQR)] age was 35.8 (29.9–42.5) years; CD4 count was 147 (50–248) cells/mm³; and pre-treatment HIV RNA was 100,000 (34,045–301,075) copies/mL. Factors associated with pre-treatment HIV RNA <100,000 copies/mL were age <30 years [OR 1.40 vs. 41–50 years; 95% confidence interval (CI) 1.10–1.80, p = 0.01], body mass index >30 kg/m² (OR 2.4 vs. <18.5 kg/m²; 95% CI 1.1–5.1, p = 0.02), anemia (OR 1.70; 95% CI 1.40–2.10, p < 0.01), CD4 count >350 cells/mm³ (OR 3.9 vs. <100 cells/mm³; 95% CI 2.0–4.1, p < 0.01), total lymphocyte count >2000 cells/mm³ (OR 1.7 vs. <1000 cells/mm³; 95% CI 1.3–2.3, p < 0.01), and no prior AIDS-defining illness (OR 1.8; 95% CI 1.5–2.3, p < 0.01). Receiver-operator characteristic (ROC) analysis yielded area under the curve of 0.70 (95% CI 0.67–0.72) among derivation patients and 0.69 (95% CI 0.65–0.74) among validation patients. A cut off score >25 yielded the sensitivity of 46.7%, specificity of 79.1%, positive predictive value of 67.7%, and negative predictive value of 61.2% for prediction of pre-treatment HIV RNA <100,000 copies/mL among derivation patients.

A model prediction for pre-treatment HIV RNA <100,000 copies/mL produced an area under the ROC curve of 0.70. A larger sample size for prediction model development as well as for model validation is warranted.

• Abacavir
• HIV RNA
• Model
• Prediction
• Rilpivirine

• CD4-Positive T-Lymphocytes
• Cell Cycle
• Cell Death
• HIV
• Homeostasis
• Immunologic Memory
• Transcriptome

• cd4/cd8 ratio
• cd8 cell counts
• disease progression
• linear mixed model
• longitudinal data
• predicition

• Antiretroviral Therapy, Highly Active/methods
• CD4-CD8 Ratio
• CD4-Positive T-Lymphocytes/pathology
• CD8-Positive T-Lymphocytes/pathology
• Disease Progression
• Female
• Follow-Up Studies
• HIV Infections/diagnosis
• HIV Infections/drug therapy
• HIV Infections/virology
• HIV-1/genetics
• Humans
• Male
• Middle Aged
• RNA, Viral/analysis
• Retrospective Studies
• Viral Load

• African NHPs
• CCR5
• Natural hosts
• Pathogenesis
• SIV
• Transmission

Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8⁺ T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8⁺ T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4⁺ T cells. Furthermore, strong antibody responses can prevent CD8⁺ T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8⁺ T-cell responses.

• AIDS
• HIV
• T-cell escape
• mathematical model
• neutralizing antibodies

In Brazil, universal provision of antiretroviral therapy (ART) has been guaranteed free of charge to eligible HIV-positive patients since December 1996. We sought to quantify the survival benefits of ART attributable to this programme.

We used a previously published microsimulation model of HIV disease and treatment (CEPAC-International) and data from Brazil to estimate life expectancy increase for HIV-positive patients initiating ART in Brazil. We divided the period of 1997 to 2014 into six eras reflecting increased drug regimen efficacy, regimen availability and era-specific mean CD4 count at ART initiation. Patients were simulated first without ART and then with ART. The 2014-censored and lifetime survival benefits attributable to ART in each era were calculated as the product of the number of patients initiating ART in a given era and the increase in life expectancy attributable to ART in that era.

In total, we estimated that 598,741 individuals initiated ART. Projected life expectancy increased from 2.7, 3.3, 4.1, 4.9, 5.5 and 7.1 years without ART to 11.0, 17.5, 20.7, 23.0, 25.3, and 27.0 years with ART in Eras 1 through 6, respectively. Of the total projected lifetime survival benefit of 9.3 million life-years, 16% (or 1.5 million life-years) has been realized as of December 2014.

Provision of ART through a national programme has led to dramatic survival benefits in Brazil, the majority of which are still to be realized. Improvements in initial and subsequent ART regimens and higher CD4 counts at ART initiation have contributed to these increasing benefits.

• Brazil
• HIV
• Latin America
• highly active antiretroviral therapy
• modelling
• survival

HIV-1 escape from CTL is predictable based on the Human Leukocyte Antigen (HLA) class I alleles expressed by the host. As such, HIV-1 sequences circulating in a population of hosts will harbor escape mutations specific to the HLA alleles of that population. In theory, this should increase the frequency of escape mutation transmission to persons expressing the restricting HLA allele, thereby compromising host immunity to the incoming HIV-1 strain. However, the clinical impact of infection with HIV-1 containing immune escape mutations has not conclusively been demonstrated. Japan’s population features limited HLA diversity which is driving population-level HIV adaptation: for example, >60% of Japanese express HLA-A*24:02 and its associated Nef-Y135F escape mutation represents the population consensus. As such, Japan is an ideal population in which to examine this phenomenon. Here, we combine genetic and immunological analyses to identify A*24:02-positive individuals likely to have been infected with Y135F-containing HIV-1. Over a ~5 year follow-up, these individuals exhibited significantly lower CD4 counts compared to individuals inferred to have been infected with wild-type HIV-1. Our results support a significant negative clinical impact of pathogen adaptation to host pressures at the population level.

• Adaptation, Biological
• Adolescent
• Adult
• Aged
• Alleles
• Antigen Presentation
• CD4 Lymphocyte Count
• Disease Progression
• Female
• Genotype
• HIV Infections/immunology
• HIV Infections/virology
• HIV-1/classification
• HIV-1/physiology
• Histocompatibility Antigens Class I/chemistry
• Histocompatibility Antigens Class I/genetics
• Histocompatibility Antigens Class I/immunology
• Host-Pathogen Interactions/immunology
• Humans
• Male
• Middle Aged
• Mutation
• Phylogeny
• Retrospective Studies
• Viral Load
• Young Adult
• nef Gene Products, Human Immunodeficiency Virus/genetics
• nef Gene Products, Human Immunodeficiency Virus/immunology

The possibility of incorporating generics into combination antiretroviral therapy and breaking apart once-daily single-tablet regimens (STRs), may result in less efficacious medications and/or more complex regimens with the expectation of marked monetary savings. A modeling approach that assesses the merits of such policies in terms of lifelong costs and health outcomes using adherence and effectiveness data from real-world U.S. settings.

A comprehensive computer-based microsimulation model was developed to assess the lifetime health (life expectancy and quality adjusted life-years—QALYs) and economic outcomes in HIV-1 infected patients initiating STRs compared with multiple-table regimens including generic medications where possible (gMTRs). The STRs considered included tenofovir disoproxil fumarate/emtricitabine and efavirenz or rilpivirine or elvitegravir/cobicistat. gMTRs substitutions included each counterpart to STRs, including generic lamivudine for emtricitabine and generic versus branded efavirenz.

Life expectancy is estimated to be 1.301 years higher (discounted 0.619 QALY gain) in HIV-1 patients initiating a single-tablet regimen in comparison to a generic-based multiple-table regimen. STRs were associated with an average increment of $26,547.43 per patient in medication and $1,824.09 in other medical costs due to longer survival which were partially offset by higher inpatients costs ($12,035.61) with gMTRs treatment. Overall, STRs presented incremental lifetime costs of $16,335.91 compared with gMTRs, resulting in an incremental cost-effectiveness ratio of $26,383.82 per QALY gained.

STRs continue to represent good value for money under contemporary cost-effectiveness thresholds despite substantial price reductions of generic medications in the U. S.

Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4⁺ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab–infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection.

We report that administration of the intraluminal antibiotic Rifaximin and the gut-focused anti-inflammatory drug Sulfasalazine to acutely SIV-infected pigtailed macaques is associated with a transient disruption of the vicious circle of inflammation-microbial translocation-immune activation which is pathognomonic to pathogenic HIV/SIV infection and drives HIV disease progression and non-AIDS comorbidities in HIV-infected patients. This therapeutic approach resulted in transient lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4⁺ T cells and lower levels of hypercoagulation biomarkers throughout acute SIV infection. Our results thus support the use of therapeutic approaches to reduce microbial translocation, improve the clinical outcome of HIV-infected patients receiving antiretroviral therapy and prevent non-AIDS comorbidities. Our results also reinforce the importance of early therapeutic management of HIV infection.

• Animals
• Anti-Bacterial Agents/pharmacology
• Anti-Inflammatory Agents/pharmacology
• Flow Cytometry
• Immunohistochemistry
• Inflammation/drug therapy
• Inflammation/etiology
• Intestines/drug effects
• Intestines/microbiology
• Macaca nemestrina
• Male
• Rifamycins/pharmacology
• Rifaximin
• Simian Acquired Immunodeficiency Syndrome/complications
• Simian Acquired Immunodeficiency Syndrome/drug therapy
• Simian Immunodeficiency Virus
• Sulfasalazine/pharmacology
• Thrombophilia/drug therapy
• Thrombophilia/etiology

• P01 AI088564 NIAID NIH HHS
• R01 HL117715 NHLBI NIH HHS
• R01 HL123096 NHLBI NIH HHS
• R01 RR025781 NCRR NIH HHS