Alcohol Use and HIV Prevention Among Personnel in the Belize Defence Force.

To evaluate the effect of a peer-based risk reduction project on alcohol use and sexual behavior within Belize Defence Force personnel. We used a quasi-experimental, mixed quantitative and qualitative methods design to evaluate project outcomes. Two serial cross-sectional surveys were conducted [baseline (n = 126) and 6-month follow-up (n = 128)] using computer assisted self-interview. Semistructured interviews were collected from 12 peer counselors 3 months after the beginning of the project. The proportion of respondents screening positive for alcohol dependence decreased significantly from 80 % at preintervention to 66 % at postintervention (p = 0.045), and the percentage of respondents reporting that they normally drink alcohol before work decreased from 11 to 3 % (p = 0.013). Alcohol abuse and dependency scores correlated positively with the overall number of sexual partners in both male and female respondents. There was a slight decrease in the percentage of female respondents' reporting inconsistent condom use for vaginal sex (baseline 100 %, follow-up 83 %, p = 0.088), but there was no appreciable change reported in condom use among male respondents. Qualitative findings suggest that techniques to reduce the quantity of alcohol consumed were a salient focus of peer counselors, and administrative barriers can readily mitigate implementation of such interventions. In this evaluation of a risk reduction program with the BDF, we found evidence of a reduction in types of alcohol use from baseline to follow-up. Alcohol-related risk reductions carry implications for reducing sexual risk behavior in military personnel. Future research with stronger experimental design strategies may better elucidate how substance use reduction is linked with sexual risk reduction in military personnel.

Injection preparation filtration and health concerns among indigenous people who inject methamphetamine.

Introduction: Injecting methamphetamine poses significant health risks, but little is known about how methamphetamine injectors filter their injection preparations and experience related health concerns. Methods: A chain-referral sample of Indigenous people who inject methamphetamine (n = 30) was recruited and semistructured interviews were conducted to collect information on filtration practices and health concerns. Results: Filtration of the injection preparation was described by 53% of injectors. Elevated levels of concern for kidney disease, cancer and heart disease were observed among those who filtered their preparations (ranging from 50 to 56.3%). Concern about liver disease was the most frequent concern among those who filtered their preparations (62.5%) and was elevated in comparison to those who did not use filters (7.1%). Grouped logistic regression revealed a positive association between filtration of the injection preparation and overall health concerns expressed by injectors, after adjusting for gender and age. The marginal posterior distribution of the adjusted odds ratio for filtration of the injection preparation had a posterior median = 35.7, and 95% HPD interval = (5.1, 512.4). Discussion: Results illustrate a positive relationship between filtration of the injection preparation and health concerns among Indigenous people who inject methamphetamine. This likely reflects the use of filtration to reduce harms, and further research is needed to understand the full scope of prevention that may be associated with filtration of methamphetamine injection preparations.

Ethics guidelines for environmental epidemiologists: 2023 revision.

Recognition of the importance to environmental epidemiology of ethical and philosophical deliberation led, in 1996, to the establishment of Ethics Guidelines for the profession. In 1999, these guidelines were adopted by the International Society for Environmental Epidemiology. The guidelines were revised in 2012 and again in 2023 to ensure continued relevance to the major issues facing the field. Comprising normative standards of professional conduct, the guidelines are structured into four subsections: (1) obligations to individuals and communities who participate in research; (2) obligations to society; (3) obligations regarding funders/sponsors and employers; and (4) obligations to colleagues. Through the 2023 revision of the Ethics Guidelines, the International Society for Environmental Epidemiology seeks to ensure the highest possible standards of transparency and accountability for the ethical conduct of environmental epidemiologists engaged in research and public health practice.

Linking peers, patients, and providers: a qualitative study of a peer integration program for hard-to-reach patients living with HIV/AIDS.

For HIV-positive individuals living in socially vulnerable circumstances, the complexities of accessing and navigating healthcare system can be overwhelming. Peer-driven interventions (PDIs) are increasingly being recognized as effective ways of addressing barriers to HIV care in the USA. The present study is a qualitative investigation of barriers, challenges, and facilitators to implementation of a peer integration program at three health centers in the USA. Findings reveal that health center staff and HIV-positive patients support the integration of HIV-positive peers on multidisciplinary healthcare teams. However, challenges related to peer-clinician communication and the risk of emotional burnout for peers may hinder program efficacy and sustainability. Practical implications and suggestions for improving the peer integration program in light of these findings are also discussed.

Sexual risk behavior and symptoms of historical loss in American Indian men.

Native Americans in the United States are not typically regarded as a most at-risk population for HIV or other sexually transmitted infections (STIs), despite emerging evidence which suggests otherwise. As a result, Native Americans lack access to key prevention services and programs. In planning prevention programs for this unique population, however, it is important to take into account the cultural factors that may be implicated in health risk behaviors. Historical Loss is a type of historical trauma that has been reported in Native Americans, and which may be related to health behaviors. We examined whether Historical Loss was associated with sexual risk behaviors in a sample of 120 American Indian men living in Fort Peck Reservation in northeastern Montana who completed questions regarding Historical Loss and sexual risk behaviors. Symptoms of Historical Loss that reflected Anxiety/Depression and Anger/Avoidance were associated with an increased likelihood of individuals' having sex with multiple concurrent partners. Health interventions that aim to address HIV/STI prevention should take symptoms of Historical Loss into account, as Historical Loss could be a potential factor that will mitigate HIV, STI, and pregnancy prevention efforts in this population.

Condom use following a pilot test of the Popular Opinion Leader intervention in the Barbados Defence Force.

Worldwide, military personnel have been recognized as a population at elevated risk for sexually transmitted infections and HIV. However, few evidence based behavioral interventions for the prevention of HIV and STIs have been rigorously evaluated in military personnel. We adapted the Popular Opinion Leaders (POL) intervention and piloted the adapted program with the Barbados Defence Force at one military base in Barbados. Popular Opinion Leaders were selected and trained to focus conversations on condom use. Behavioral questionnaires were administered using audio computer-assisted self interview at baseline (n = 256) and 6-month follow-up (n = 303). Mid-point focus groups were conducted with a sample of 15 POLs at a 3 month mid-point assessment. Quantitative data showed moderate increases in condom use at 6-months, and significant uptake of condom use during oral-genital contact in female personnel. A subgroup analysis suggests that this change was partially mediated by post-intervention changes in injunctive norms surrounding condom use in women. Focus groups revealed that POLs were heavily focusing on condom demonstrations, condom provision within social networks, speaking with coworkers about pleasure associated with condom use, and that the most common venues for conversations included those where alcohol was consumed. During the intervention, POLs dispersed from the intervention site as a result of normal personnel movement across bases, resulting in our having to use a pre and post intervention design across the population. It is likely that larger effect sizes would be observed in efforts that account for the natural dispersion of personnel across bases.

Toward a social theory of sexual risk behavior among men in the Armed Services: understanding the military occupational habitus.

Worldwide, military personnel have been recognized as a population at elevated risk for sexually transmitted infections (STIs) and HIV; however, it is not well understood how the military occupation itself is implicated in the production of sexual risk behavior. Using qualitative and quantitative data collected from the Belize Defense Force (BDF), we employed a grounded theoretical framework and the Bourdieusian concept of the field and habitus to clarify how the military occupation is implicated in structuring aspects of sexual risk behaviors among personnel. We focus results on in-depth qualitative interviews conducted with 15 male-identified BDF personnel. We identify and describe how two field elements, namely operational tempo and ongoing exposure to occupational hazards, are occupationally specific field elements implicated in the production of sexual risk behavior through the mediating matrix of the military class habitus. Our findings demonstrate a conceptual clarity regarding the institutional field and habitus through which military personnel make sense of and act on the risk of bodily harm with regard to their own sexual behaviors. We conclude by outlining our theoretical concept so that it can be directly applied in public health efforts in order to leverage military occupational field elements for the purpose of HIV and STI prevention.

Evidence of secular trends during the COVID-19 pandemic in a stepped wedge cluster randomized trial examining sexual and reproductive health outcomes among Indigenous youth.

BACKGROUND: Nen UnkUmbi/EdaHiYedo ("We Are Here Now," or NE) is an intervention to prevent STIs, HIV, HCV, and teen pregnancy among Assiniboine and Sioux youth of the Fort Peck Reservation in the state of Montana in the USA. A cluster-randomized stepped-wedge design (SWD) trial is used to evaluate NE, where clusters are schools. The purpose of this study is to evaluate whether there is evidence of a secular trend associated with the COVID-19 pandemic. METHODS: The original study design is a cluster-randomized stepped-wedge design (SWD), in which five schools that youth from Fort Peck attend are the clusters to be randomized into the intervention one at a time, with all schools eventually being randomized to the intervention across three steps. N/E is a 5-year study involving 456 15- to 18-year-old youth. For this study, we use a mixed quantitative and qualitative methods approach to understand how the COVID-19 pandemic may have been associated with the study's primary outcome variables. Data were drawn from the first cluster exposed to the intervention and one control cluster that did not yet receive the intervention during the period in which COVID-19 mitigation efforts were being implemented. A pre-post COVID questionnaire was added to core measures administered, and semistructured qualitative interviews were conducted with youths regarding their perceptions of how the pandemic altered their sexual behaviors. RESULTS: One hundred eighteen youth responded to the questionnaire and 31 youth participated in semistructured qualitative interviews. Youth reporting having sex with less people due to COVID-19 reported more sex acts (incident rate ratio (IRR)=3.6, 95% CI 1.6-8.1) in comparison to those who did not report having sex with less people, and youth who reported having sex with the same amount of people due to COVID-19 reported less sex acts (IRR=0.31, 95% CI 0.14-0.7) in comparison to those who did not report having sex with the same amount of people. Youth reporting having sex less times due to COVID-19 experienced a greater number of sex acts in comparison to those who did not report having sex less times (IRR=2.7, 1.2-6.4). Results suggest that more sexually active individuals reported perceiving having sex with less people and less frequent engagement in sex during the pandemic. It is possible that the COVID-19 pandemic period was associated with a truncation in the distribution of sexual activity that would bias an estimate of the intervention's effect. CONCLUSION: Findings suggest evidence of a secular trend. This trend must be accounted for at trial end, and sensitivity analyses are recommended. Documenting and reporting on these findings encourages transparent reporting during the implementation of a SWD trial during a global pandemic, and informs endline analyses. TRIAL REGISTRATION: This trial is registered with the Clinical trials registry of the US National Library of Medicine at the National Institutes of Health (NIH). It was registered on October 1, 2018. The study presented in this manuscript is funded by NIH National Institute on Minority Health and Health Disparities (NIMHD), Award # R01MD012761-01, Elizabeth Rink (Principal Investigator). The study's ClinicalTrials.gov number is NCT03694418.

A culturally appropriate method for validating self-reported drug administration among indigenous people who use injection drugs.

Compared with other racial/ethnic groups in the United States (US), American Indians/Alaska Natives have one of the fastest climbing rates of drug overdose deaths involving stimulants. Validating the substances self-reported by Indigenous people who use injection drugs (IPWIDs) can present logistical and cultural challenges. While the collection of biospecimens (e.g., urine, blood, hair follicle) can be one way to cross-validate the substances self-reported by IPWIDs, the collection of biospecimens has been historically problematic when conducting substance use research with Indigenous North Americans. In our National Institutes of Health (NIH)-supported pilot research conducted with IPWIDs, we have documented low willingness to provide a biospecimen to a research team. This article demonstrates an alternative method for validating self-reported substances injected by IPWIDs that does not require the extraction of biospecimens from Indigenous bodies and spaces. The method described includes:•Collecting used, unwashed syringes from IPWIDs at the time of behavioral assessment,•Sampling the used syringe by washing the syringe needle/barrel with methanol,•Analyzing the samples with gas chromatography mass spectrometry (GC-MS) and liquid chromatography coupled to triple-quadrupole mass spectrometry (LC-QQQ-MS). This method offers a more culturally appropriate alternative to validate substances self-reported by IPWIDs during behavioral assessments.

Unsettling Settler Colonialism in Research: Strategies Centering Native American Experience and Expertise in Responding to Substance Misuse and Co-occurring Sexual Risk-Taking, Alcohol-Exposed Pregnancy, and Suicide Prevention Among Young People.

Native American (NA) populations in the USA (i.e., those native to the USA which include Alaska Natives, American Indians, and Native Hawaiians) have confronted unique historical, sociopolitical, and environmental stressors born of settler colonialism. Contexts with persistent social and economic disadvantage are critical determinants of substance misuse and co-occurring sexual risk-taking and suicide outcomes, as well as alcohol exposed pregnancy among NA young people (i.e., adolescents and young adults). Despite intergenerational transmission of resistance and resiliencies, NA young people face continued disparities in substance misuse and co-occurring outcomes when compared to other racial and ethnic groups in the USA. The failure in progress to address these inequities is the result of a complex set of factors; many of which are structural and rooted in settler colonialism. One of these structural factors includes barriers evident in health equity research intended to guide solutions to address these disparities yet involving maintenance of a research status quo that has proven ineffective to developing these solutions. Explicitly or implicitly biased values, perspectives, and practices are deeply rooted in current research design, methodology, analysis, and dissemination and implementation efforts. This status quo has been supported, intentionally and unintentionally, by researchers and research institutions with limited experience or knowledge in the historical, social, and cultural contexts of NA communities. We present a conceptual framework illustrating the impact of settler colonialism on current research methods and opportunities to unsettle its influence. Moreover, our framework illustrates opportunities to resist settler colonialism in research. We then focus on case examples of studies from the Intervention Research to Improve Native American Health program, funded by the NIH, that impact substance use and co-occurring health conditions among NA young people.

Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters.

PURPOSE: To examine how the timing of hypoxic exposure results in specific childhood outcomes and whether there is a differential effect by sex. METHODS: A sample of 10,879 prospectively followed pregnancies was drawn from the Boston and Providence sites (New England, NE) of the National Collaborative Perinatal Project. Based on placental pathology, we developed and validated a measure of probable chronic placental hypoxia (CHP) and contrasted the effects of acute perinatal hypoxia on age 7 emotional, behavioral, and cognitive outcomes. RESULTS: Perinatal hypoxia had a significant impact on multiple behavioral and cognitive outcomes in boys and girls by age 7, in contrast to probable CHP which had a differential effect on girls and boys such that there was decreased verbal IQ and increased inhibition in females alone. CONCLUSIONS: Findings underscore the importance of considering the timing of obstetric complications and offspring sex in investigations of the impact of fetal and perinatal hypoxia on offspring's outcomes throughout the life course.

Retrospective Assessment of Human-Chemical Interactions in Health-Disparity Populations: A Process Evaluation of Life History Calendars.

Life-history calendars (LHCs) can produce retrospective data regarding numerous events, exposures, and sequences that have occurred across participants' lifespans. In this mixed-quantitative-and-qualitative-methods study, processes of LHC administration were evaluated in two populations experiencing health disparities: foreign-born agricultural workers (n = 41) and Indigenous people who used injection drugs (IPWIDS) (n = 40). LHC administrator and participant perspectives were elicited during follow-up survey activities. In both agricultural workers and IPWIDs, over half of participants reported that the LHC made it easier to remember things about the past, and participant age was associated with cumulative experience in different domains of interest. Qualitative findings suggested that data-collector training and the development of concise interview guides are critical for improving LHC data quality. Participants described ethical themes, including utilitarian, cathartic, and reflective aspects, of LHC participation. Future iterations of the LHC may benefit from providing free-form and open-ended spaces for participants to reflect on the LHC activity following LHC administration.

Adaptations Due to the COVID-19 Pandemic in a Community-Based Participatory Research Randomized Control Trial Examining Sexual and Reproductive Health Outcomes among American Indian Youth.

In this manuscript, we present changes in study design and analytical strategy due to the COVID-19 pandemic for Nen UnkUmbi/EdaHiYedo ("We Are Here Now," or NE). NE is a community-based participatory research multi-level randomized control trial using a stepped wedge design to address sexual and reproductive health disparities among American Indian youth. Adaptations in NE's research design, data collection, and analysis due to the COVID-19 pandemic were made based on meetings with tribally based research team members and outside non-Indigenous researchers involved in NE, as well as the study's Community Advisory Board and the Data Safety Monitoring Board. Based on these iterative discussions, decisions were made to: 1) reorganize the sequence of NE's stepped wedge design clusters, and 2) include additional quantitative and qualitative data collection and analysis in the research design that specifically addressed the impact of COVID-19 on the research participants. These adaptations have the potential to foster greater scientific knowledge in understanding how to address unanticipated 3-way interaction effects in randomized control trials with tribal communities. Findings can also contribute to understanding how public health disasters impact sexual and reproductive health among American Indian youth.

Rationale, Design, and Methods for Nen Unkumbi/Edahiyedo ("We Are Here Now"): A Multi-Level Randomized Controlled Trial to Improve Sexual and Reproductive Health Outcomes in a Northern Plains American Indian Reservation Community.

American Indian (AI) youth in the United States experience disproportionate sexual and reproductive health (SRH) disparities relative to their non-Indigenous, white counterparts, including increased rates of sexually transmitted infections (STIs), earlier sexual debut, increased rates of teen birth, and reduced access to SRH services. Past research shows that to improve SRH outcomes for AI youth in reservation communities, interventions must address complex factors and multiple levels of community that influence sexual risk behaviors. Here, we describe development of a multi-level, multi-component randomized controlled trial (RCT) to intervene upon SRH outcomes in a Northern Plains American Indian reservation community. Our intervention is rooted in a community based participatory research framework and is evaluated with a stepped wedge design that integrates 5 reservation high schools into a 5-year, cluster-randomized RCT. Ecological Systems Theory was used to design the intervention that includes (1) an individual level component of culturally specific SRH curriculum in school, (2) a parental component of education to improve parent-child communication about SRH and healthy relationships, (3) a community component of cultural mentorship, and (4) a systems-level component to improve delivery of SRH services from reservation healthcare agencies. In this article we present the rationale and details of our research design, instrumentation, data collection protocol, analytical methods, and community participation in the intervention. Our intervention builds upon existing community strengths and integrates traditional Indigenous knowledge and values with current public health knowledge to reduce SRH disparities.

A Pilot Study of Polysubstance Use Sequences across the Lifespan among Assiniboine and Sioux People Who Use Injection Drugs.

Compared with other racial/ethnic groups in the United States, American Indians/Alaska Natives have the highest rates of acute Hepatitis C Virus (HCV) infection, the highest HCV-related mortality, and one of the fastest climbing rates of drug overdose deaths involving stimulants. In this pilot study, a life history calendar was administered to Indigenous people who use injection drugs (IPWIDs) to understand sequences of polysubstance use across the lifespan. 40 IPWIDs completed a questionnaire and life history calendar. Social sequence analysis was used to examine patterns in sequential phenomena among substances reported over years of the lifespan. Most participants (55%) began injecting substances before the age of 21, 62.5% shared syringes with others, and 45% had ever been diagnosed with HCV. An appreciably large increase in the use of stimulants occurred between the year prior to and following injection initiation (33% to 82%). A three-cluster solution distinguished younger IPWIDs transitioning into polysubstance use involving stimulants and/or narcotic analgesics from adults using narcotic analgesics with stimulants over longer periods of time, and adults most focused on stimulant use over time. Findings from this pilot study contribute to an understanding of how methamphetamine injection plays a role in the HCV epidemic among IPWIDs.

Vaginal microbiota of American Indian women and associations with measures of psychosocial stress.

Molecular-bacterial vaginosis (BV) is characterized by low levels of vaginal Lactobacillus species and is associated with higher risk of sexually transmitted infections (STI). Perceived psychosocial stress is associated with increased severity and persistence of infections, including STIs. American Indians have the highest rates of stress and high rates of STIs. The prevalence of molecular-BV among American Indian women is unknown. We sought to evaluate measures of psychosocial stress, such as historic loss (a multigenerational factor involving slavery, forced removal from one's land, legally ratified race-based segregation, and contemporary discrimination) and their association with the vaginal microbiota and specific metabolites associated with BV, in 70 Northwestern Plains American Indian women. Demographics, perceived psychosocial stressors, sexual practices, and known BV risk factors were assessed using a modified version of the American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project survey. Self-collected mid-vaginal swabs were profiled for bacterial composition by 16S rRNA gene amplicon sequencing and metabolites quantified by targeted liquid-chromatography mass spectrometry. Sixty-six percent of the participants were classified as having molecular-BV, with the rest being either dominated by L. crispatus (10%) or L. iners (24%). High levels of lifetime trauma were associated with higher odds of having molecular-BV (adjusted Odds Ratio (aOR): 2.5, 95% Credible Interval (CrI): 1.1-5.3). Measures of psychosocial stress, including historic loss and historic loss associated symptoms, were significantly associated with lifestyle and behavioral practices. Higher scores of lifetime trauma were associated with increased concentrations of spermine (aFC: 3.3, 95% CrI: 1.2-9.2). Historic loss associated symptoms and biogenic amines were the major correlates of molecular-BV. Historical loss associated symptoms and lifetime trauma are potentially important underlying factors associated with BV.

Indigenous standpoint theory as a theoretical framework for decolonizing social science health research with American Indian communities.

Theoretical frameworks rooted in Western knowledge claims utilized for public health research in the social sciences are not inclusive of American Indian communities. Developed by Indigenous researchers, Indigenous standpoint theory builds from and moves beyond Western theoretical frameworks. We argue that using Indigenous standpoint theory in partnership with American Indian communities works to decolonize research related to American Indian health in the social sciences and combats the effects of colonization in three ways. First, Indigenous standpoint theory aids in interpreting how the intersections unique to American Indians including the effects of colonization, tribal and other identities, and cultural context are linked to structural inequalities for American Indian communities. Second, Indigenous standpoint theory integrates Indigenous ways of knowing with Western research orientations and methodologies in a collaborative process that works to decolonize social science research for American Indians. Third, Indigenous standpoint theory promotes direct application of research benefits to American Indian communities.

Sexual risk behavior among military personnel stationed at border-crossing zones in the Dominican Republic.

OBJECTIVE: To estimate the prevalence of sexual risk behaviors among military personnel stationed along major border-crossing zones between the Dominican Republic and Haiti. METHODS: From November 2008 to January 2009, behavioral surveys were administered to 498 active duty military personnel stationed along the three largest border-crossing zones on the western border of the Dominican Republic. Participants were selected using systematic random sampling and asked about their sexual behavior over the past 12 months, alcohol use, and mental health. RESULTS: Forty-one percent reported having casual sex during the past 12 months, 37% of men had a history of having sex with a commercial sex worker (19% during the past 12 months), and 7% of men reported a history of having sex with a transmigrating Haitian (6% during the past 12 months). Among sexually non-monogamous respondents (51%), inconsistent condom use exceeded 60% for those engaging in anal, vaginal, or oral sex. Fifteen percent reported using sexual coercion during the past 12 months. CONCLUSIONS: Sexual risk behaviors were prevalent among military personnel stationed along border-crossing zones between the Dominican Republic and Haiti. Prevention programs targeted at military personnel in this region should incorporate sexual coercion and mental health as key elements of their HIV prevention programs.

A needs assessment of clients with HIV in a home-based care program in Guyana.

OBJECTIVE: To assess the needs of clients in a home-based care (HBC) program aimed at improving the quality of lives of people living with HIV in Region 4 of Guyana (Demerara-Mahaica region) following their involvement with the HBC program, volunteers, and nurse providers. DESIGN AND SAMPLE: A cross-sectional analysis of a needs assessment conducted through a verbally administered questionnaire. We collected a cross-sectional sample of 84 HBC clients living with HIV from Region 4 in Guyana. MEASURES: Respondents were administered a questionnaire that asked questions regarding the demographics; services received; quality of service delivery; and mental health and substance abuse. RESULTS: The services most commonly received by respondents included nutritional assessment and counseling, HIV prevention education, emotional support, hygiene education, support for antiretroviral adherence, and support for HIV disclosure. Respondents reported further need of referrals to income-generation opportunities, food and nutritional supplement support, and support for children. Forty-two percent of the respondents screened positive for probable depression, and 37% of respondents screened positive for being at risk for a drinking problem. CONCLUSIONS: While a substantial portion of needs were addressed by the HBC program, outstanding needs included linking people living with HIV to income-generation opportunities, food support, mental health, and services for children. We suggest that mental health and substance use services be factored into HIV programming and that referral systems be strengthened to ensure access to support services for people living with HIV.

Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells.

BACKGROUND: Virus-specific CD8(+) T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8(+) T cells with a "polyfunctional" profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8(+) T cell responses on the single-epitope level over time, starting in primary HIV-1 infection. METHODS AND FINDINGS: We longitudinally analyzed the polyfunctional epitope-specific CD8(+) T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8(+) T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8(+) T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%-72%) to 76% (56%-95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%-75%) to 56% (42%-70%) (SD of the effect size 0.18) (p < 0.05). CONCLUSION: These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.