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Background: Pig‐tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm. Methods: Eighteen female PTMs were evaluated. Blood was collected 1–24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers. Results: Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index. Conclusions: Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs. [ABSTRACT FROM AUTHOR]

Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/106 cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/106 cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP. [ABSTRACT FROM AUTHOR]

Vaginal SHIVSF162P3 acquisition in pigtail macaques ( Macaca nemestrina) is dependent on time point during the menstrual cycle. Susceptibility is higher around menstruation and lower at ovulation in mid cycle. This complicates the design of repeat low-dose (RLD) SHIV exposure studies because virus challenges given during low susceptibility periods have lower chances to infect. To account for fluctuating susceptibility, we analyzed menstrual cycles rather than exposures until infection following virus challenges. We first reanalyzed infection data of 41 macaques receiving placebo or no treatment during once ( n=18) or twice ( n=23) weekly virus exposures. The same number of cycles was required for infection with either challenge frequency, while it took a median four or six challenges for once or twice weekly exposures, respectively. More virus challenges to infection likely reflect frequent unsuccessful exposures in frequently exposed animals. When reanalyzing two previously reported biomedical HIV intervention studies, we found 1% tenofovir gel was 74% or 86% efficacious based on cycles or exposures ( p=0.019 or p=0.003, respectively, Fisher's exact test), while 1% raltegravir gel was 84% or 89 % efficacious, respectively ( p=0.047 or p=0.031). Evaluating the number of menstrual cycles rather than exposures until infection can account for varying susceptibility during the menstrual cycle. Our observations have implications for future study designs such as planning the frequency of virus exposures. Menstrual cycle analysis may also avoid potential overestimation of efficacy against vaginal challenges during low susceptibility periods in the cycle that are unlikely to cause infection. [ABSTRACT FROM AUTHOR]

The repeat low-dose virus challenge model is commonly used in nonhuman primate studies of HIV transmission and biomedical preventions. For some viruses or challenge routes, it is uncertain whether the repeated exposure design might induce virus-directed innate or adaptive immunity that could affect infection or viremic outcomes. Retrospective cohorts of male Indian rhesus ( n=40) and female pigtail ( n=46) macaques enrolled in repeat low-dose rectal or vaginal SHIVSF162p3 challenge studies, respectively, were studied to compare the relationship between the number of previous exposures and peak plasma SHIV RNA levels or viral load area under the curve (AUC), surrogate markers of viral control. Repeated mucosal exposures of 10 or 50 TCID50 of virus for rectal and vaginal exposures, respectively, were performed. Virus levels were measured by quantitative reverse-transcriptase real-time PCR. The cumulative number of SHIVSF162p3 exposures did not correlate with observed peak virus levels or with AUC in rectally challenged rhesus macaques [peak: rho (ρ)=0.04, p=0.8; AUC: ρ=0.33, p=0.06] or vaginally challenged pigtail macaques (peak: ρ=−0.09, p=0.7; AUC: ρ=0.11, p=0.6). Infections in these models occur independently of exposure history and provide assurance that neither inoculation route nor number of exposures required for infection correlates with postinfection viremia. These data also indicate that both the vaginal and rectal repeated low-dose virus exposure models using SHIVSF162p3 provide a reliable system for nonhuman primate studies. [ABSTRACT FROM AUTHOR]

Background: Preexposure prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that Simian/Human Immunodeficiency Virus chimera (SHIV)-specific T-cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T-cell chemo-vaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure., Methods: Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild-type (WT) SHIVSF162P3 (n = 24) or a clonal derivative with the tenofovir (TFV) K65R drug-resistant mutation (n = 12). PrEP consisted of oral Truvada (n = 6, WT), TFV vaginal gel (n = 6, K65R), or TFV intravaginal ring (n = 6, WT). The remaining animals were PrEP-inexperienced controls (n = 12, WT; n = 6, K65R). SHIV-specific T cells were identified and characterized using interferon γ Enzyme-Linked ImmunoSpot (ELISPOT) and multiparameter flow cytometry., Results: Of 9 animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, 8 (88.9%) developed virus-specific T-cell responses. T cells were in CD4 and CD8 compartments, reached up to 4900 interferon γ-producing cells per million peripheral blood mononuclear cells, and primarily pol directed. In contrast, the replication-impaired K65R virus did not induce detectable T-cell responses, likely reflecting the need for adequate replication., Conclusions: Virus-specific T-cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and after PrEP warrants further investigation.