emtricitabine--tenofovir-disoproxil-fumarate-drug-combination and Viremia

Monocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined. Here, we define more completely monocyte phenotype both prior to ART initiation and during 48 weeks of ART.. Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained at baseline (prior to ART initiation) and at weeks 12, 24, and 48 of treatment from 29 patients participating in ACTG clinical trial A5248, an open label study of raltegravir/emtricitibine/tenofovir administration. For comparison, cryopreserved PBMCs were obtained from 15 HIV-1 uninfected donors, each of whom had at least two cardiovascular risk factors. Thawed samples were stained for monocyte subset markers (CD14 and CD16), HLA-DR, CCR2, CX3CR1, CD86, CD83, CD40, CD38, CD36, CD13, and CD163 and examined using flow cytometry.. In untreated HIV-1 infection there were perturbations in monocyte subset phenotypes, chiefly a higher frequency and density (mean fluorescence intensity-MFI) of HLA-DR (%-p = 0.004, MFI-p = .0005) and CD86 (%-p = 0.012, MFI-p = 0.005) expression and lower frequency of CCR2 (p = 0.0002) expression on all monocytes, lower CCR2 density on inflammatory monocytes (p = 0.045) when compared to the expression and density of these markers in controls' monocytes. We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls. After ART, these perturbations tended to improve, with decreasing expression and density of HLA-DR and CD86, increasing CCR2 density on inflammatory monocytes, and increasing expression and density of CX3CR1 on patrolling monocytes.. In HIV-1 infected patients, ART appears to attenuate the high levels of activation (HLA-DR, CD86) and to increase expression of the chemokine receptors CCR2 and CX3CR1 on monocyte populations. Circulating monocyte phenotypes are altered in untreated infection and tend to normalize with ART; the role of these cells in the inflammatory environment of HIV-1 infection warrants further study.

Topics: Adult; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Cell Separation; CX3C Chemokine Receptor 1; Drug Combinations; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Female; Flow Cytometry; HIV Infections; HIV Integrase Inhibitors; HIV-1; HLA-DR Antigens; Humans; Immunophenotyping; Male; Middle Aged; Monocytes; Raltegravir Potassium; Receptors, CCR2; Receptors, Chemokine; Viral Load; Viremia

Pre-exposure prophylaxis (PrEP) with daily Truvada [a combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] is a novel HIV prevention strategy recently found to prevent HIV transmission among men who have sex with men and heterosexual couples. Acute infection in adherent persons who fail PrEP will inevitably occur under concurrent antiretroviral therapy, thus raising questions regarding the potential impact of PrEP on early viral dynamics. We investigated viral evolution dynamics in a macaque model of PrEP consisting of repeated rectal exposures to SHIV162P3 in the presence of PrEP.. Four macaques were infected during daily or intermittent PrEP with FTC or FTC/TDF, and five were untreated controls. SHIV env sequence evolution was monitored by single genome amplification with phylogenetic and sequence analysis. Mean nucleotide divergence from transmitted founder viruses calculated 17 weeks (range = 12-20) post peak viremia was significantly lower in PrEP failures than in control animals (7.2 × 10-3 compared to 1.6 × 10-2 nucleotide substitutions per site per year, respectively, p < 0.0001). Mean virus diversity was also lower in PrEP failures after 17 weeks (0.13% vs. 0.53% in controls, p < 0.0001).. Our results in a macaque model of acute HIV infection suggest that infection during PrEP limits early virus evolution likely because of a direct antiviral effect of PrEP and/or reduced target cell availability. Reduced virus diversification during early infection might enhance immune control by slowing the selection of escape mutants.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Deoxycytidine; Disease Models, Animal; Drug Combinations; Drug Evaluation, Preclinical; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Evolution, Molecular; Gene Products, env; Genetic Variation; Genome, Viral; Macaca mulatta; Male; Organophosphorus Compounds; Phylogeny; RNA, Viral; Sequence Analysis, DNA; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Viremia

The impact of pre-exposure prophylaxis (PrEP) with antiretrovirals on breakthrough HIV or SHIV infection is not fully documented. We addressed the hypothesis that SHIV(SF162P3) infection despite active PrEP results in altered early immune parameters, compared with untreated infection.. Eleven rhesus macaques were infected during repeated, rectal, low-dose SHIV(SF162P3) exposures while receiving concurrent oral PrEP (Truvada [n = 2] or GS7340 [n = 4]) or as untreated controls (n = 5). We measured SHIV RNA, inflammatory cytokines, CD4 cells, and SHIV-specific and memory T cells until 20 weeks after peak viremia.. SHIV infection during PrEP resulted in 100-fold lower peak viremia and lower IL-15, IL-18, and IL-1Ra levels, compared with controls (P < .05; Wilcoxon rank-sum test). Unlike controls, PrEP-treated macaques showed no significant CD4 cell count reduction during acute infection and developed more SHIV-specific central memory T cells, relative to controls. After in vivo CD8 cell depletion, viral load increased to similar levels, indicating that CD8 cells were critical for viral control in both groups.. PrEP with antiretrovirals has beneficial effects on early SHIV infection even when infection is not prevented. Although long-term immune control could not be examined in this SHIV infection model, our results suggest that PrEP results in improved early disease parameters in breakthrough infections.

Topics: Adenine; Alanine; Animals; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cytokines; Deoxycytidine; Drug Combinations; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Longitudinal Studies; Macaca mulatta; Male; Organophosphorus Compounds; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Statistics, Nonparametric; Tenofovir; Viremia