Despite their importance for immunity against sexually transmitted infections (STIs), the composition of the female reproductive tract (FRT) memory CD4 T cell population in response to changes in the local tissue environment during the menstrual cycle remains poorly defined. Here we show that across humans, non-human primates (NHP), and mice, FRT CD4 T cells comprise distinct subsets corresponding to migratory memory (TMM) and resident memory (TRM) cells. TMM display tissue-itinerant trafficking characteristics, restricted FRT tissue distribution, with distinct transcriptional properties and effector responses to infection. CD4 T cell subset fluctuations synchronized with cycle-driven proinflammatory changes within the local tissue environment and oral administration of a CCR5 antagonist inhibited cycle phase-specific migratory T cell surveillance. This study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of memory T cell defense at the site of STI exposure. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

BACKGROUND: The menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time. METHODS: Blood and vaginal lavage samples were collected from 18 pig-tailed macaques to evaluate immune changes over reproductive cycles, and from 5 additional animals undergoing repeated vaginal exposures to simian HIV (SHIV). Peripheral blood mononuclear cell (PBMC) samples from healthy women (n = 10) were prospectively collected over the course of a menstrual cycle to profile T cell populations. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Plasma progesterone was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression on CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was monitored in plasma by RT-PCR. Immune measures were compared using generalized estimating equations (GEE). FINDINGS: Macaques cycle-phases were associated with fluctuations in systemic immune properties and a type-1 inflammatory T cell response with corresponding CCR5+ memory CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis identified CCR5 oscillation frequencies synchronized with reproductive cycles. In a repetitive low-dose vaginal challenge model, productive SHIV(163P3) infection only occurred during intervals of mounting type-1 T cell responses (n = 5/5). Finally, we identify similar type-1 inflammatory T cell responses over the menstrual cycle are occurring in healthy women. INTERPRETATION: These data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drives bystander CCR5+ CD4 T cell recruitment and HIV susceptibility in the female reproductive tract. FUNDING: This study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407 to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454]). DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services.

OBJECTIVE: In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to "waning," or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or "frailty." We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials. METHODS: Using multiplicative risk reduction, we developed a mathematical formulation for computing disease incidence and the incidence rate ratio (IRR) as a function of frailty and waning. We designed study scenarios, which held study-related factors constant, varied waning and frailty parameters and measured the change in disease incidence, IRR, and statistical power. RESULTS: We found that frailty alone can impact disease incidence over time. However, frailty has minimal impact on the IRR. The factor that has the greatest influence on the IRR is intervention efficacy and the degree to which it is projected to wane. We also found that even moderate waning can cause an unacceptable decrease in statistical power while the impact of frailty on statistical power is minimal. DISCUSSION: We conclude that frailty has minimal impact on trial results relative to intervention efficacy. Study resources would, therefore, be better spent on efforts to keep the intervention efficacy constant throughout the trial (e.g., enhancing the vaccine schedule or promoting treatment adherence).

Over 1.1 million Americans are living with human immunodeficiency virus (HIV), and African-American youth and young adults are disproportionately affected. Condoms are the most effective prevention tool, yet data regarding condom use patterns for African-American college youth are lacking. To inform and strengthen HIV prevention strategies with African-American college-age youth, we surveyed students attending 24 historically Black colleges and universities regarding condom use patterns. Students were administered anonymous questionnaires online to explore knowledge, attitudes, and practices related to condom use during last sexual intercourse (LSI). Among 824 sexually active respondents (51.8% female, median age 20 years, 90.6% heterosexuals), 526 (63.8%) reported condom use during LSI. Students who used condoms for disease prevention, whose mothers completed high school or had some college education or completed college were more likely to have used a condom during LSI. Spontaneity of sexual encounters, not feeling at risk of HIV, and partner-related perceptions were associated with condom non-use during LSI (p<0.05). Over a third of our college youth sample did not use a condom during LSI and may benefit from increased condom education efforts. These efforts should highlight condoms' effectiveness in protection from HIV. Future HIV education and prevention strategies with similar groups of young adults should explore the implications of maternal education, clarify perceptions of HIV risk, and consider strategies that increase consistent condom use to interrupt sexual transmission of HIV.

OBJECTIVE: African American young adults are disproportionately affected by the HIV/AIDS epidemic and often unaware of their personal risk for HIV. Historically black colleges and universities (HBCUs) enroll 25% of college-educated African American young adults and can play an important role in HIV prevention. We examined HIV/AIDS knowledge of students at HBCUs to inform and strengthen our HIV prevention efforts at HBCUs. METHODS: African American undergraduate HBCU students completed online surveys assessing HIV/AIDS knowledge and behaviors, and we analyzed data to assess their knowledge and behaviors. RESULTS: A total of 1,051 of 1,230 surveys completed (85.4%) were analyzable. Eighty-two percent of students had average/high HIV knowledge scores. Seventy-nine percent of students surveyed perceived themselves to be at low risk for HIV infection; 64% of those who had at least two or more sex partners had not used a condom at last sex encounter. In the final model, significant independent effects were identified for average/high knowledge of HIV risk, including agreeing with assessing a potential partner's HIV risk by all of the five actions listed (adjusted odds ratio [AOR] = 2.7, 95% confidence interval [CI] 1.7, 4.3) and never using a needle to inject drugs (AOR=5.6, 95% CI 3.2, 9.7). CONCLUSIONS: Educating students about effectively assessing sex partner risk will improve HIV knowledge and prevention efforts at HBCUs.

In the context of monitoring and improving CDC-funded HIV prevention programs, we describe HIV tests and infections, provision of results, previous HIV tests, and risk behaviors for young (aged 13-29) men of color who have sex with men who received HIV tests at five community-based organizations. Of 1,723 tests provided, 2.1% were positive and 75.7% of positives were previously unaware of their infection. The highest positivity rate was among men aged 25-29 (4.7%). Thirty-four percent of tests were provided to men who were tested for the first time. Over half the tests (53.2%) were provided to men who reported sex with a person of unknown HIV status, and 34% to men who reported sex with an anonymous partner. Continued and more focused prevention efforts are needed to reach and test young men of color who have sex with men and to identify previously undiagnosed HIV infections among this target population.

BACKGROUND: Recent analyses have shown increases in combined annual HIV diagnosis rates for Asians and Pacific Islanders (API). METHODS: Using surveillance data from 33 states and 4 dependent areas we investigated the epidemiology of HIV among API during 2001-2008. RESULTS: HIV diagnoses for API during 2001-2008 were predominantly among persons age 30-39 years (40%) and males (78%). The primary risk factor for males was sexual contact with males (78%) and for females, heterosexual contact (86%). API were the only racial/ethnic groups with a statistically significant estimated annual percentage increase (4.4%) in HIV diagnoses over the time period. Thirty-seven percent of HIV diagnoses among API progressed to AIDS in <12 months, with significantly greater likelihood among those 30 years and older. Survival was lower among API with AIDS diagnosis after 49 years of age, and was higher among persons with AIDS whose primary risk factor for infection was heterosexual contact. CONCLUSIONS: In contrast to other racial/ethnic groups, API were the only groups to show a significant increase in HIV diagnoses. A clearer understanding of the reasons for this trend is needed, so that appropriate interventions can be selected and adapted to prevent increased HIV prevalence among API in the U.S.