Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia.

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ T cells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ T cells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ T cells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

Identification of a Clade-Specific HLA-C*03:02 CTL Epitope GY9 Derived from the HIV-1 p17 Matrix Protein.

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues E62, T142, and E151 in the HLA-C*03:02 binding groove and positions p3, p6, and p9 on the GY9 epitope are crucial in shaping and stabilizing the epitope binding. Our findings support the growing evidence of the contribution of HLA-C molecules to HIV-1 control and provide a prospect for vaccine strategies.

T Cell Homeostasis Disturbances in a Cohort of Long-Term Elite Controllers of HIV Infection.

Elite controllers (ECs) are people living with HIV (PLWH) able to control HIV replication without antiretroviral therapy and have been proposed as a model of a functional HIV cure. Much evidence suggests that this spontaneous control of HIV has a cost in terms of T cell homeostasis alterations. We performed a deep phenotypic study to obtain insight into T cell homeostasis disturbances in ECs maintaining long-term virologic and immunologic control of HIV (long-term elite controllers; LTECs). Forty-seven PLWH were included: 22 LTECs, 15 non-controllers under successful antiretroviral therapy (onART), and 10 non-controllers not receiving ART (offART). Twenty uninfected participants (UCs) were included as a reference. T cell homeostasis was analyzed by spectral flow cytometry and data were analyzed using dimensionality reduction and clustering using R software v3.3.2. Dimensionality reduction and clustering yielded 57 and 54 different CD4 and CD8 T cell clusters, respectively. The offART group showed the highest perturbation of T cell homeostasis, with 18 CD4 clusters and 15 CD8 clusters significantly different from those of UCs. Most of these alterations were reverted in the onART group. Interestingly, LTECs presented several disturbances of T cell homeostasis with 15 CD4 clusters and 13 CD8 clusters different from UC. Moreover, there was a specific profile of T cell homeostasis alterations associated with LTECs, characterized by increases in clusters of naïve T cells, increases in clusters of non-senescent effector CD8 cells, and increases in clusters of central memory CD4 cells. These results demonstrate that, compared to ART-mediated control of HIV, the spontaneous control of HIV is associated with several disturbances in CD4 and CD8 T cell homeostasis. These alterations could be related to the existence of a potent and efficient virus-specific T cell response, and to the ability to halt disease progression by maintaining an adequate pool of CD4 T cells.

Patient and health provider costs of integrated HIV, diabetes and hypertension ambulatory health services in low-income settings - an empirical socio-economic cohort study in Tanzania and Uganda.

BACKGROUND: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. METHODS: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. RESULTS: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. CONCLUSION: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

The Antibodiome-Mapping the Humoral Immune Response to HIV.

PURPOSE OF REVIEW: The design of an HIV vaccine remains an elusive but top priority. Data from the non-human primate model and the first moderately protective HIV vaccine trial (RV144) point to a role for qualitative changes in humoral immune functions in protection from infection. Here, we review the current understanding of the antibody response throughout HIV infection, the known correlates of protection, and current strategies to manipulate antibodies to put an end to the epidemic. RECENT FINDINGS: Recent studies point to innate immune-recruiting antibody function in preventing infection as well as controlling viremia following infection. These data have begun to inform next-generation design of HIV vaccines and antibody therapies by uncovering new viral targets and antibody architectures to improve potency and breadth. Emerging data illustrate a role for innate immune recruiting-antibodies in conferring protection against HIV infection as well as promoting viral control and clearance, offering an unprecedented opportunity to modulate and improve antibody function to fight HIV more effectively.

HIV programme sustainability in Southern and Eastern Africa and the changing role of external assistance for health.

High human immunodeficiency virus (HIV)-prevalence countries in Southern and Eastern Africa continue to receive substantial external assistance (EA) for HIV programming, yet countries are at risk of transitioning out of HIV aid without achieving epidemic control. We sought to address two questions: (1) to what extent has HIV EA in the region been programmed and delivered in a way that supports long-term sustainability and (2) how should development agencies change operational approaches to support long-term, sustainable HIV control? We conducted 20 semi-structured key informant interviews with global and country-level respondents coupled with an analysis of Global Fund budget data for Malawi, Uganda, and Zambia (from 2017 until the present). We assessed EA practice along six dimensions of sustainability, namely financial, epidemiological, programmatic, rights-based, structural and political sustainability. Our respondents described HIV systems' vulnerability to donor departure, as well as how development partner priorities and practices have created challenges to promoting long-term HIV control. The challenges exacerbated by EA patterns include an emphasis on treatment over prevention, limiting effects on new infection rates; resistance to service integration driven in part by 'winners' under current EA patterns and challenges in ensuring coverage for marginalized populations; persistent structural barriers to effectively serving key populations and limited capacity among organizations best positioned to respond to community needs; and the need for advocacy given the erosion of political commitment by the long-term and substantive nature of HIV EA. Our recommendations include developing a robust investment case for primary prevention, providing operational support for integration processes, investing in local organizations and addressing issues of political will. While strategies must be locally crafted, our paper provides initial suggestions for how EA partners could change operational approaches to support long-term HIV control and the achievement of universal health coverage.

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Once a death sentence, HIV is now considered a manageable chronic disease due to the development of antiretroviral therapy (ART) regimens with minimal toxicity and a high barrier for genetic resistance. While highly effective in arresting AIDS progression and rendering the virus untransmissible in people living with HIV (PLWH) with undetectable viremia (U=U) [1, 2]), ART alone is incapable of eradicating the "reservoir" of resting, latently infected CD4+ T cells from which virus recrudesces upon treatment cessation. As of 2022 estimates, there are 39 million PLWH, of whom 86% are aware of their status and 76% are receiving ART [3]. As of 2017, ART-treated PLWH exhibit near normalized life expectancies without adjustment for socioeconomic differences [4]. Furthermore, there is a global deceleration in the rate of new infections [3] driven by expanded access to pre-exposure prophylaxis (PrEP), HIV testing in vulnerable populations, and by ART treatment [5]. Therefore, despite outstanding issues pertaining to cost and access in developing countries, there is strong enthusiasm that aggressive testing, treatment, and effective viral suppression may be able to halt the ongoing HIV epidemic (ie, UNAIDS' 95-95-95 targets) [6-8]; especially as evidenced by recent encouraging observations in Sydney [9]. Despite these promising efforts to limit further viral transmission, for PLWH, a "cure" remains elusive; whether it be to completely eradicate the viral reservoir (ie, cure) or to induce long-term viral remission in the absence of ART (ie, control; Figure 1). In a previous salon hosted by Pathogens and Immunity in 2016 [10], some researchers were optimistic that a cure was a feasible, scalable goal, albeit with no clear consensus on the best route. So, how are these cure strategies panning out? In this commentary, 8 years later, we will provide a brief overview on recent advances and failures towards identifying determinants of viral persistence and developing a scalable cure for HIV. Based on these observations, and as in the earlier salon, we have asked several prominent HIV cure researchers for their perspectives.

Erratum to: Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

[This corrects the article DOI: 10.20411/pai.v8i2.665.].

T-Follicular-Like CD8+ T Cell Responses in Chronic HIV Infection Are Associated With Virus Control and Antibody Isotype Switching to IgG.

T cell responses are considered critical for the in vivo control of HIV, but the contribution of different T cell subsets to this control remains unclear. Using a boosted flow cytometric approach that is able to differentiate CD4+ and CD8+ T cell Th1/Tc1, Th2/Tc2, Th17/Tc17, Treg and Tfh/Tfc-like HIV-specific T cell populations, we identified CD8+ Tfc responses that were related to HIV plasma viral loads and associated with rate of antibody isotype class switching to IgG. This favorable balance towards IgG responses positively correlated with increased virus neutralization, higher avidity of neutralizing antibodies and more potent antibody-dependent cell cytotoxicity (ADCC) in PBMCs from HIV controllers compared to non-controllers. Our results identified the CD8+ Tfc-like T-cell response as a component of effective virus control which could possibly be exploited therapeutically.

HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control.

Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and a transcriptionally TRM-like profile distinct from blood CD8+ T-cells. In PLWH, CD8+ TRM-like cells are expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8+ T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIV-specific CD8+ TRM-like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs.

HIV Antibody Profiles in HIV Controllers and Persons With Treatment-Induced Viral Suppression.

Introduction: Low HIV viral load is associated with delayed disease progression and reduced HIV transmission. HIV controllers suppress viral load to low levels in the absence of antiretroviral treatment (ART). We used an antibody profiling system, VirScan, to compare antibody reactivity and specificity in HIV controllers, non-controllers with treatment-induced viral suppression, and viremic non-controllers. Methods: The VirScan library contains 3,384 phage-displayed peptides spanning the HIV proteome. Antibody reactivity to these peptides was measured in plasma from a Discovery Cohort that included 13 elite controllers, 27 viremic controllers, 12 viremic non-controllers, and 21 non-controllers who were virally suppressed on ART. Antibody reactivity to selected peptides was also assessed in an independent cohort of 29 elite controllers and 37 non-controllers who were virally suppressed on ART (Validation Cohort) and in a longitudinal cohort of non-controllers. Results: In the Discovery Cohort, 62 peptides were preferentially targeted in HIV controllers compared to non-controllers who were virally suppressed on ART. These specificities were not significantly different when comparing controllers versus viremic non-controllers. Aggregate reactivity to these peptides was also high in elite controllers from the independent Validation Cohort. The 62 peptides formed seven clusters of homologous epitopes in env, gag, integrase, and vpu. Reactivity to one of these clusters located in gag p17 was inversely correlated with viral load set point in an independent cohort of non-controllers. Conclusions: Antibody reactivity was low in non-controllers suppressed on ART, but remained high in viremic controllers despite viral suppression. Antibodies in controllers and viremic non-controllers were directed against epitopes in diverse HIV proteins; higher reactivity against p17 peptides was associated with lower viral load set point. Further studies are needed to determine if these antibodies play a role in regulation of HIV viral load.

Processed HIV prognostic dataset for control experiments.

This paper provides a control dataset of processed prognostic indicators for analysing drug resistance in patients on antiretroviral therapy (ART). The dataset was locally sourced from health facilities in Akwa Ibom State of Nigeria, West Africa and contains 14 attributes with 1506 unique records filtered from 3168 individual treatment change episodes (TCEs). These attributes include sex, before and follow-up CD4 counts (BCD4, FCD4), before and follow-up viral load (BRNA, FRNA), drug type/combination (DTYPE), before and follow-up body weight (Bwt, Fwt), patient response to ART (PR), and classification targets (C1-C5). Five (5) output membership grades of a fuzzy inference system ranging from very high interaction to no interaction were constructed to model the influence of adverse drug reaction (ADR) and subsequently derive the PR attribute (a non-fuzzy variable). The PR attribute membership clusters derived from a universe of discourse table were then used to label the classification targets as follows: C1=no interaction, C2=very low interaction, C3=low interaction, C4=high interaction, and C5=very high interaction. The classification targets are useful for building classification models and for detecting patients with ADR. This data can be exploited for the development of expert systems, for useful decision support to treatment failure classification [1] and effectual drug regimen prescription.

Reasons People Living with HIV Might Prefer Oral Daily Antiretroviral Therapy, Long-Acting Formulations, or Future HIV Remission Options.

A growing body of research is beginning to elucidate reasons people living with HIV (PLWHIV) might prefer oral daily antiretroviral treatment (ART) compared with emerging long-acting ART (LA-ART) or HIV remission strategies under investigation. Our objective is to provide qualitative insights into the reasons why PLWHIV might prefer one of these HIV control therapies over others. From May to August 2018, we implemented a semistructured cross-sectional survey of PLWHIV in the United States to better understand patient preferences around various HIV treatment and remission options. Using free text, respondents were asked to explain why they preferred one HIV control option over the other two. We analyzed responses to the open-ended survey questions on reasons for preferring oral daily ART versus LA-ART versus HIV remission strategies using conventional content analysis. The results showed that PLWHIV preferred oral daily ART because of its familiarity and known safety and efficacy profile, whereas those who preferred LA-ART would value the convenience it offers. Finally, HIV remission strategies would be preferred to avoid taking ART altogether. The qualitative results provide insights into reasons why PLWHIV in the United States might prefer oral daily ART versus novel therapies. More importantly, they provide information to better align HIV virological control strategies with end-user perspectives. To make informed choices around evolving HIV therapeutics, PLWHIV and HIV care providers would benefit from decision tools to better assess options and trade-offs. More research is needed on how best to effectively support PLWHIV and HIV care providers in shared decision-making.

The network structure of sex partner meeting places reported by HIV-infected MSM: Opportunities for HIV targeted control.

Baltimore, Maryland ranks among U.S. cities with the highest incidence of HIV infection among men who have sex with men (MSM). HIV screening at sex partner meeting places or venues frequented by MSM with new diagnoses and/or high HIV viral load may reduce transmission by identifying and linking infected individuals to care. We investigated venue-based clustering of newly diagnosed MSM to identify high HIV transmission venues. HIV surveillance data from MSM diagnosed between October 2012-June 2014 and reporting ≥1 sex partner meeting place were examined. Venue viral load was defined according to the geometric mean viral load of the cluster of cases that reported the venue and classified as high (>50,000 copies/mL), moderate (1500-50,000 copies/mL), and low (<1500 copies/mL). 143 MSM provided information on ≥1 sex partner meeting place, accounting for 132 unique venues. Twenty-six venues were reported by > 1 MSM; of these, a tightly connected cluster of six moderate viral load sex partner meeting places emerged, representing 66% of reports. Small, dense networks of moderate to high viral load venues may be important for targeted HIV control among MSM.

Elite controller CD8+ T cells exhibit comparable viral inhibition capacity, but better sustained effector properties compared to chronic progressors.

Mechanisms modulating HIV-specific CD8+ T cell-mediated viral inhibition are not well defined. To delineate features of effective control, we compared the ability of CD8+ T cells from HIV ECs and CPs to inhibit HIV ex vivo. ECs showed superior inhibition compared to HAART-treated or untreated CPs in a typical VIA in which CD8+ T cells are rested 3 d before use (P = 0.025). In contrast, comparable antiviral activity was observed in freshly thawed cells. Rested CD8+ T cells underwent apoptosis with preferential loss of HIV-specific cells. EC CD8+ T cells showed greater capacity to sustain polyfunctionality ex vivo compared with those of CPs, and incubation of CD8+ T cells with IL-15 augmented inhibition. These results indicate that superior ex vivo inhibition of viral replication by CD8+ T cells from ECs is associated with enhanced retention of functional qualities and that in vitro antiviral function is enhanced by IL-15.

Transactional sex in the fishing communities along Lake Victoria, Kenya: a catalyst for the spread of HIV.

The study describes the nature, context and implications of a unique form of transactional sexual relationships in the fishing communities along Lake Victoria in Kisumu County, Kenya. We conducted 12 focus group discussions and 17 key informant interviews among fishermen, fishmongers and fish transporters in Kisumu. Women fishmongers in the fishing communities commonly form relationships with fishermen, which are often sexual, as part of the jaboya system, wherein women who wish to sell fish in the market secure the rights to purchase the fish caught by the fishermen. Due to the nature and context of the sexual intercourse, sex typically occurs in a hurried manner, often without preparation or protection. Thus, by engaging in a web of these relationships, conducted in contexts that compromise their ability to practice safer sex, men and women in these fishing communities are at increased risk of HIV.