Globally, in 2022, about 350,000 new HIV infections occurred among young people aged 15–24 years, with 140,000 infections among adolescents aged 10–19 [[1]Joint United Nations Programme on HIV/AIDS (UNAIDS)The path that ends AIDS: UNAIDS global AIDS update 2023. UNAIDS, Geneva2023https://www.unaids.org/sites/default/files/media_asset/2023-unaids-global-aids-update_en.pdfGoogle Scholar]. About two thirds of all infections among young people occurred in sub-Saharan Africa, and high HIV incidence rates have been observed, particularly in eastern and southern Africa [[2]Birdthistle I. Tanton C. Tomita A. et al.Recent levels and trends in HIV incidence rates among adolescent girls and young women in ten high-prevalence African countries: A systematic review and meta-analysis.Lancet Glob Health. 2019; 7: e1521-e1540https://doi.org/10.1016/S2214-109X(19)30410-3Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,[3]Rosenberg N.E. Shook-Sa B.E. Liu M. et al.Adult HIV-1 incidence across 15 high-burden countries in sub-Saharan Africa from 2015 to 2019: A pooled analysis of nationally representative data.Lancet HIV. 2023; 10: e175-185https://doi.org/10.1016/S2352-3018(22)00328-9Abstract Full Text Full Text PDF Scopus (6) Google Scholar]. However, some young people, particularly young members of key populations, are at substantial risk of HIV infection in all regions globally, and young people in low- and middle-income countries have poorer outcomes along each step of the HIV continuum of prevention and treatment than older adults [[4]Goldstein M. Archary M. Adong J. et al.Systematic review of mHealth interventions for adolescent and young adult HIV prevention and the adolescent HIV continuum of care in low to middle income countries.AIDS Behav. 2023; 27: 94-115https://doi.org/10.1007/s10461-022-03840-0Crossref Scopus (6) Google Scholar]. For instance, the ImPrEP study in Brazil, Mexico, and Peru found high incidence among their young participants, with about 2% incidence among transgender women and those aged 18–24 [[5]Veloso V.G. Cáceres C.F. Hoagland B. et al.Same-day initiation of oral pre-exposure prophylaxis among gay, bisexual, and other cisgender men who have sex with men and transgender women in Brazil, Mexico, and Peru (ImPrEP): A prospective, single-arm, open-label, multicentre implementation study.Lancet HIV. 2023; 10: e84-e96https://doi.org/10.1016/S2352-3018(22)00331-9Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. In the Philippines, rising new HIV infections are driven by infections among men who have sex with men and transgender women, one third of which occurring among those aged under 25 [[6]Department of Health (DOH)Philippines | Epidemiology Bureau. HIV/AIDS and ART registry of the Philippines: November 2022. DOH Philippines, Manila2022https://www.aidsdatahub.org/resource/hiv-aids-and-art-registry-philippines-november-2022Google Scholar]. Moreover, about half of people who inject drugs are estimated to be aged under 25 in Eastern Europe and Latin America [[7]Degenhardt L. Peacock A. Colledge S. et al.Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: A multistage systematic review.Lancet Glob Health. 2017; 5: e1192-e1207https://doi.org/10.1016/S2214-109X(17)30375-3Abstract Full Text Full Text PDF PubMed Scopus (916) Google Scholar], and HIV acquisition risk may be higher among people who start injecting drugs at an early age [[8]Oguya F.O. Kenya P.R. Ongecha F. et al.Rapid situational assessment of people who inject drugs (PWID) in Nairobi and coastal regions of Kenya: A respondent driven sampling survey.BMC Public Health. 2021; 21: 1549Crossref Scopus (4) Google Scholar,[9]Ganapathi L. McFall A.M. Srikrishnan A.K. et al.Young people who inject drugs in India have high HIV incidence and behavioural risk: A cross-sectional study.J Int AIDS Soc. 2019; 22e25287Crossref PubMed Scopus (11) Google Scholar]. Evidence-based HIV prevention options are needed to address high HIV incidence among adolescents and young people, including comprehensive harm reduction programs for people who use drugs. Oral pre-exposure prophylaxis (PrEP) has been recommended by the World Health Organization (WHO) for all people at substantial risk of HIV infection since 2015. The WHO recommendation did not specify a minimum age for PrEP use, although some national regulatory authorities specify a minimum weight [[10]Kimmel A. Schaefer R. Watson L. et al.Access to pre-exposure prophylaxis for HIV prevention among young people aged 15-24: A global policy review.Presented at: 24th International AIDS Conference, Montreal, Canada, 29 July - 2 August. 2022Google Scholar]. Oral PrEP use has been increasing globally since the WHO recommendation [[11]Schaefer R. Schmidt H.-M.A. Ravasi G. et al.Adoption of guidelines on and use of oral pre-exposure prophylaxis: A global summary and forecasting study.Lancet HIV. 2021; 8: e502-e510Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]; however, the scale of PrEP use among young people is unknown. Using preliminary data from the Global AIDS Monitoring process [[12]Joint United Nations Programme on HIV/AIDS (UNAIDS)Global AIDS Monitoring 2023: Indicators and questions for monitoring progress on the 2021 Political Declaration on HIV and AIDS.2022https://www.unaids.org/en/resources/documents/2022/global-aids-monitoring-guidelinesGoogle Scholar], 42 countries reported about 180,000 PrEP users aged 15–19 in 2022, and 45 countries reported about 300,000 PrEP users aged 20–24. Nearly half of these were reported in just one country (South Africa), although, given the lack of reporting from many countries, these data likely underestimate the extent of PrEP use by young people and do not reflect PrEP persistence and effective use [[13]Celum C.L. Bukusi E.A. Bekker L.G. et al.PrEP use and HIV seroconversion rates in adolescent girls and young women from Kenya and South Africa: The POWER demonstration project.J Int AIDS Soc. 2022; 25e25962Crossref Scopus (24) Google Scholar]. Young people face significant barriers to accessing sexual and reproductive health services, including PrEP. An analysis of 70 national PrEP guideline documents found that 19 countries specified a minimum age for PrEP use, which was 18 years or older in 14 of these [[10]Kimmel A. Schaefer R. Watson L. et al.Access to pre-exposure prophylaxis for HIV prevention among young people aged 15-24: A global policy review.Presented at: 24th International AIDS Conference, Montreal, Canada, 29 July - 2 August. 2022Google Scholar]. Even where there are no age restrictions for PrEP, there may be age and parental consent restrictions around accessing other sexual and reproductive health services [[14]Govender K. Masebo W.G.B. Nyamaruze P. et al.HIV prevention in adolescents and young people in the eastern and Southern African region: A review of key challenges impeding actions for an effective response.Open AIDS J. 2018; 12: 53-67Crossref PubMed Scopus (36) Google Scholar]. Lack of knowledge [[15]Chimbindi N. Mthiyane N. Zuma T. et al.Antiretroviral therapy based HIV prevention targeting young women who sell sex: A mixed method approach to understand the implementation of PrEP in a rural area of KwaZulu-Natal, South Africa.AIDS Care. 2022; 34: 232-240Crossref Scopus (7) Google Scholar], stigma, and discrimination [[16]Rosengren A.L. Lelutiu-Weinberger C. Woodhouse E.W. et al.A Scoping review of HIV pre-exposure prophylaxis stigma and implications for stigma-reduction interventions for men and transwomen who have sex with men.AIDS Behav. 2021; 25: 2054-2070Crossref Scopus (30) Google Scholar], among other factors, may further add structural barriers to accessing PrEP by young people. Where young people initiate PrEP, they may face additional challenges to effectively using it during periods of risk [[17]Allison B.A. Widman L. Stewart J.L. et al.Adherence to pre-exposure prophylaxis in adolescents and young adults: A systematic review and meta-analysis.J Adolesc Health. 2022; 70: 28-41Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,[18]Koss C.A. Charlebois E.D. Ayieko J. et al.Uptake, engagement, and adherence to pre-exposure prophylaxis offered after population HIV testing in rural Kenya and Uganda: 72-week interim analysis of observational data from the SEARCH study.Lancet HIV. 2020; 7: e249-e261Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar], including lack of risk perception [[19]Haberer J.E. Mugo N. Bukusi E.A. et al.Understanding pre-exposure prophylaxis adherence in young women in Kenya.J Acquir Immune Defic Syndr. 2022; 89: 251-260Crossref PubMed Scopus (6) Google Scholar], alcohol use [[20]Kayesu I. Mayanja Y. Nakirijja C. et al.Uptake of and adherence to oral pre-exposure prophylaxis among adolescent girls and young women at high risk of HIV-infection in Kampala, Uganda: A qualitative study of experiences, facilitators and barriers.BMC Womens Health. 2022; 22: 440Crossref Scopus (9) Google Scholar], homelessness [[21]Biello K.B. Bazzi A.R. Mimiaga M.J. et al.Perspectives on HIV pre-exposure prophylaxis (PrEP) utilization and related intervention needs among people who inject drugs.Harm Reduct J. 2018; 15: 55Crossref PubMed Scopus (74) Google Scholar], social norms around sexuality [[22]Skovdal M. Clausen C.L. Magoge-Mandizvidza P. et al.How gender norms and 'good girl' notions prevent adolescent girls and young women from engaging with PrEP: Qualitative insights from Zimbabwe.BMC Wom Health. 2022; 22: 344Crossref Scopus (5) Google Scholar], and intimate partner violence [[23]Cabral A. Baeten J M. Ngure K. et al.Intimate partner violence and Self-reported pre-exposure prophylaxis interruptions among HIV-Negative partners in HIV Serodiscordant couples in Kenya and Uganda.J Acquir Immune Defic Syndr. 2018; 77: 154-159Crossref PubMed Scopus (41) Google Scholar]. New PrEP options may overcome some uptake and effective use challenges by young people. In 2021, WHO recommended offering the dapivirine vaginal ring (DVR) to women at substantial risk of HIV and, in 2022, long-acting injectable cabotegravir (CAB-LA) was recommended. Values and preferences research suggests there is interest in long-acting PrEP methods among young people but also diverse preferences across populations and regions [[24]Lorenzetti L. Dinh N. van der Straten A. et al.Systematic review of the values and preferences regarding the use of injectable pre-exposure prophylaxis to prevent HIV acquisition.J Int AIDS Soc. 2023; 26e26107Crossref Scopus (2) Google Scholar], although most studies evaluated hypothetical rather than enacted preferences. Allowing young people to choose their preferred PrEP option has the potential to make PrEP more acceptable, thus improving uptake and effective use. However, there are significant gaps in research regarding new PrEP products for young people, particularly adolescents. Clinical trials evaluating the DVR did not include women under the age of 18 years and found no reduction in HIV risk among young women aged 18–21 [[25]Rosenberg Z., Nel A., Van Baelen B., et al. Pooled efficacy analysis of two phase III trials of dapivirine vaginal ring for the reduction of HIV-1 infection risk in HIV-uninfected women in sub-saharan Africa July. Paris: Presented at: 9th IAS Conference on HIV Science, Paris, France, 23-26 July 2017.Google Scholar], who tended to have lower levels of effective use. Further analyses suggest higher efficacy of the DVR among young women who used the ring consistently [[26]Brown E.R. Hendrix C.W. van der Straten A. et al.Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV-1 acquisition: A secondary analysis from a randomized, placebo-controlled trial.J Int AIDS Soc. 2020; 23e25634Crossref Scopus (42) Google Scholar]. More recently, results from the REACH study demonstrated that, with targeted support, high levels of consistent DVR use can be achieved among women aged 16–21 [[27]Ngure K, Nair G, Szydlo D, et al. Choice and Adherence to dapivirine ring or oral PrEP by young African women in REACH. Presented at: CROI, Virtual, 12-16 February 2022.Google Scholar] and that, among women who used both the ring and oral PrEP, a majority preferred the DVR. Similarly, clinical trials of CAB-LA did not include adolescents under 18 but CAB-LA was found highly efficacious at preventing HIV acquisition among young women aged 18–24 [[28]Delany-Moretlwe S. Hughes J.P. Bock P. et al.Cabotegravir for the prevention of HIV-1 in women: Results from HPTN 084, a phase 3, randomised clinical trial.Lancet. 2022; 399: 1779-1789https://doi.org/10.1016/S0140-6736(22)00538-4Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar] and men who have sex with men and transgender women aged 18–29 [[29]Landovitz R.J. Donnell D. Clement M.E. et al.Cabotegravir for HIV prevention in cisgender men and transgender women.N Engl J Med. 2021; 385: 595-608Crossref PubMed Scopus (287) Google Scholar]. Small-scale studies on the safety and acceptability of CAB-LA among adolescents are underway. The results from REACH on DVR use by young people and the high efficacy of CAB-LA among young adults are encouraging. However, implementation research is needed on how PrEP services can reach young people, particularly adolescents and young members of key populations, how services can offer a choice of PrEP options and ensure informed decision-making, and how services can support young people to use PrEP effectively. A significant number of studies are planned to offer a choice of CAB-LA and oral PrEP, and several of these studies in sub-Saharan Africa will also offer the DVR [[30]PrEPWATCH. Implementation study tracker.https://www.prepwatch.org/resources/implementation-study-tracker/Google Scholar]. The PrEP1519 project in Brazil is unique in that it will focus on adolescent men who have sex with men and transgender women. Although several studies in sub-Saharan Africa also aim to include adolescents, these tend not to focus on young members of key populations. Nevertheless, geographies outside of eastern and southern Africa are less represented by planned projects, notably Asia, Latin America, and Eastern Europe. Moreover, there is limited focus on sex workers, trans and gender diverse populations, and people who use drugs, who could benefit from PrEP as part of comprehensive harm reduction. Young people need options for HIV prevention that include different PrEP choices (including event-driven oral PrEP for those eligible) and easy access to postexposure prophylaxis for those with recent potential exposure. However, implementation research also needs to focus on how PrEP services are delivered. Differentiated service delivery is critical to making services acceptable and accessible. Young people require youth-friendly services adapted to their needs and preferences, and WHO has recently updated guidelines on successful programming for young key populations that address their complex health and social needs [[31]World Health Organization (WHO)Consolidated guidelines on HIV, viral hepatitis and STI prevention, diagnosis, treatment and care for key populations. WHO, Geneva2022https://www.who.int/publications/i/item/9789240052390Google Scholar]. mHealth interventions may be particularly acceptable for young people [[4]Goldstein M. Archary M. Adong J. et al.Systematic review of mHealth interventions for adolescent and young adult HIV prevention and the adolescent HIV continuum of care in low to middle income countries.AIDS Behav. 2023; 27: 94-115https://doi.org/10.1007/s10461-022-03840-0Crossref Scopus (6) Google Scholar]. While the DVR can likely be relatively easily integrated into differentiated service delivery models for PrEP, such as community-based delivery, there are additional challenges with delivering differentiated services for CAB-LA that implementation science needs to explore. Given the challenges to uptake and effective use faced by young people, offering a range of HIV prevention options, including multiple PrEP products, has the potential to be particularly impactful in this population, when services are provided in an acceptable way. Coordination across studies is important to ensure learning exchange and data synthesis. For instance, close partnership between South Africa's Project PrEP and Brazil's PrEP1519, with coordination and support by WHO, facilitated cross-contextual learning and catalyzed translation of the evidence into policy and guidelines [[32]World Health Organization (WHO)Catalysing the global impact of projects to improve young people's sexual health in Brazil and South Africa.in: WHO Delivering Results and Making an Impact: Stories from the Ground. WHO, Geneva2022https://www.who.int/publications/i/item/9789240064652Google Scholar]. Such coordination will be critical to address crucial issues around new PrEP options, including safety during pregnancy and breastfeeding and drug resistance in the case of CAB-LA [[33]Schmidt H.-M.A. Rodolph M. Schaefer R. et al.Long-acting injectable cabotegravir: Implementation science needed to advance this additional HIV prevention choice.J Int AIDS Soc. 2022; 25e25963Crossref Scopus (10) Google Scholar]. Moreover, PrEP services for young people can only be impactful when structural barriers are addressed, for instance by removing legal barriers, recognizing the needs of young people in national and international guidelines, and including them in the design and delivery of services. Unitaid and the Bill & Melinda Gates Foundation have awarded grants to the World Health Organization to enable this article.

Objective: HIV remains a significant burden, despite expanding HIV prevention tools. Long-acting injectable cabotegravir (CAB-LA) is a new preexposure prophylaxis (PrEP) product. We reviewed existing evidence to determine the efficacy and safety of CAB-LA as PrEP to inform global guidelines. Design: Systematic review and meta-analysis. Methods: We systematically reviewed electronic databases and conference abstracts for citations on CAB-LA from January 2010 to September 2021. Outcomes included HIV infection, adverse events, drug resistance, pregnancy-related adverse events, and sexual behavior. We calculated pooled effect estimates using random-effects meta-analysis and summarized other results narratively. Results: We identified 12 articles/abstracts representing four multisite randomized controlled trials. Study populations included cisgender men, cisgender women, and transgender women. The pooled relative risk of HIV acquisition comparing CAB-LA to oral PrEP within efficacy studies was 0.21 (95% confidence interval: 0.07–0.61), resulting in a 79% reduction in HIV risk. Rates of adverse events were similar across study groups. Of 19 HIV infections among those randomized to CAB-LA with results available, seven had integrase strand transfer inhibitor (INSTI) resistance. Data on pregnancy-related adverse events were sparse. No studies reported on sexual behavior. Conclusions: CAB-LA is highly efficacious for HIV prevention with few safety concerns. CAB-LA may lead to an increased risk of INSTI resistance among those who have acute HIV infection at initiation or become infected while taking CAB-LA. However, results are limited to controlled studies; more research is needed on real-world implementation. Additional data are needed on the safety of CAB-LA during pregnancy (for mothers and infants) and among populations not included in the trials.

Task sharing has been one of the most important enabling policies supporting the global expansion of access to HIV testing and treatment. The WHO public health approach, which relies on delivery of antiretroviral therapy (ART) by nurses, has enabled a trebling of the number of people receiving ART during the past decade. WHO recognises that HIV pre-exposure prophylaxis (PrEP) can also be provided by nurses; however, many countries still do not have policies in place that support nurse provision of PrEP. In sub-Saharan Africa, most countries allow nurses to prescribe ART, but only a few countries have policies in place that allow nurses to prescribe PrEP. Nurseled PrEP delivery is particularly low in the Asia-Pacific region, which has some of the world's fastest growing epidemics. Even in many high-income countries, PrEP scale-up has been limited because policies often require medical doctors or specialists to prescribe. Service providers in many countries are coming to realise that scaling up access to PrEP cannot be achieved by medical doctors alone, and nurse-led PrEP delivery can help to lay the groundwork for supporting uptake of other HIV prevention approaches that will become available in the future. Countries with policies that authorise nurses to prescribe ART could be early adopters and help to pave the way for wider adoption of nurse-led PrEP delivery.

HIV diagnosis is a critical step in linking HIV-infected individuals to care and treatment and linking HIV-uninfected persons to prevention services. However, the uptake of HIV testing remains low in many countries. HIV self-screening (HIVSS) is acceptable to adults, but there is limited data on HIVSS feasibility in community programmes. This study aimed to evaluate the feasibility of HIVSS in South Africa. We conducted a prospective study that enrolled participants through mobile site, homebased, workplace and sex worker programmes in two townships from May to November 2017. Following an information session on HIVSS, interested participants were offered one of three methods of HIVSS testing: supervised, semi-supervised, and unsupervised. Participants who opted for unsupervised testing and those who tested HIV positive after semi- or supervised HIVSS were followed up telephonically or with a home visit one week after receipt of the test kit to confirm results and linkages to care. Follow-up visits were concluded when the participant indicated that they had used the kit or had accessed a confirmatory HIV test. Of the 2061 people approached, 88.2% (1818/2061) received HIV testing information. Of this group, 89% (1618/1818) were enrolled in the study and 70.0% (1133/1618) were tested for HIV with the kit. The median age was 28 (IQR:23–33) years with an even gender distribution. Of those enrolled, 43.0% (696/1618) were identified through homebased outreach, 42.5% (687/1618) through mobile sites, 7.3% (118/1618) at their workplace and 7.2% (117/1618) from sex worker programmes. A total of 68.7% (1110/1616) selected unsupervised HIVSS, whereas 6.3% (101/1616) opted for semi-supervised and 25.0% ((405/1616) chose supervised HIVSS. Overall, the HIV prevalence using the HIVSS test was 8.2% (93/1129). Of those newly diagnosed with HIV, 16% (12/75) were initiated on ART. Almost half (48.0%; 543/1131) of those tested were linked to a primary HIV test as follows: supervised (85.2%; 336/394); semi-supervised (93.8%; 91/97) and unsupervised (18.1%; 116/640). Unsupervised HIVSS was by far the most selected and utilised HIVSS method. Linkages to primary and confirmatory testing for the unsupervised HIVSS and further care were low, despite home visits and telephonic reminders.

This chapter provides a high level overview of key sexual and reproductive health (SRH) issues in adolescent health with a focus on sub-Saharan Africa. The chapter begins by providing an overview of key targets and definitions relating to adolescent SRH and then goes on to describe the heterogenous nature of SRH needs of adolescents, highlighting their often overlapping and multiple needs as well as challenges and barriers to access. The chapter then provides a synopsis of selected SRH issues, including prevalence and public health relevance, as well as a summary of evidence-based interventions. The chapter ends with controversies and challenges, as well as recommendations for future areas for research. It should be read in conjunction with Chapter 31 on HIV in adolescents.

In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.

Objective: We characterized protein-specific CD8(+) T-cell immunodominance patterns during the first year of HIV-1 infection, and their impact on viral evolution and immune control.Methods: We analyzed CD8(+) T-cell responses to the full HIV-1 proteome during the first year of infection in 18 antiretroviral-naive individuals with acute HIV-1 subtype C infection, all identified prior to seroconversion. Ex-vivo and cultured interferon-gamma ELISPOT assays were performed and viruses from plasma were sequenced within defined CTL Gag epitopes.Results: Nef-specific CD8(+) T-cell responses were dominant during the first 4 weeks after infection and made up 40% of the total responses at this time; yet, by 1 year, responses against this region had declined and Gag responses made up to 47% of all T-cell responses measured. An inverse correlation between the breadth of Gag-specific responses and viral load set point was evident at 26 weeks after infection (P = 0.0081, r = -0.60) and beyond. An inverse correlation between the number of persistent responses targeting Gag and viral set point was also identified (P = 0.01, r = -0.58). Gag-specific responses detectable by the cultured ELISPOT assay correlated negatively with viral load set point (P = 0.0013, r = -0.91). Sequence evolution in targeted and nontargeted Gag epitopes in this cohort was infrequent.Conclusions: These data underscore the importance of HIV-specific CD8(+) T-cell responses, particularly to the Gag protein, in the maintenance of low viral load levels during primary infection, and show that these responses are initially poorly elicited by natural infection. These data have implications for vaccine design strategies. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n = 120) or chronic (n = 207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r = 0.19, p = 0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p = 0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r = -0.21, p = 0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course.

BACKGROUND:Human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8(+) T-cell epitopes during and after acute viremia are lacking.METHODS:We characterized CD8(+) T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-γ enzyme-linked immunosorbent spot assay. Eleven of these had not fully seroconverted at the time of analysis. Viruses from plasma were sequenced within defined cytotoxic T-lymphocyte (CTL) cell epitopes for selected subjects.RESULTS:At approximately 28 days after estimated initial infection, CD8(+) T-cell responses were directed against an average of 3 of the 410 peptides tested (range, 0-6); 2 individuals had no detectable responses at this time. At 18 weeks, the average number of peptides targeted had increased to 5 (range 0-11). Of the 56 optimal Gag CTL epitopes sequenced, 31 were wild-type in the infecting viruses, but only 11 of 31 elicited measurable CD8(+) T-cell responses.CONCLUSIONS:These data demonstrate that the majority of CD8(+) responses are not elicited during acute HIV infection despite the presence of the cognate epitope in the infecting strain. There is a need to define factors that influence lack of induction of effective immune responses and the parameters that dictate immunodominance in acute infection.