HIV Control Research Articles

Anti-Drug Antibodies in Pigtailed Macaques Receiving HIV Broadly Neutralising Antibody PGT121.

Broadly neutralising antibodies (bNAbs) may play an important role in future strategies for HIV control. The development of anti-drug antibody (ADA) responses can reduce the efficacy of passively transferred bNAbs but the impact of ADA is imperfectly understood. We previously showed that therapeutic administration of the anti-HIV bNAb PGT121 (either WT or LALA version) controlled viraemia in pigtailed macaques with ongoing SHIV infection. We now report on 23 macaques that had multiple treatments with PGT121. We found that an increasing number of intravenous doses of PGT121 or human IgG1 isotype control antibodies (2-4 doses) results in anti-PGT121 ADA induction and low plasma concentrations of PGT121. ADA was associated with poor or absent suppression of SHIV viremia. Notably, ADA within macaque plasma recognised another human bNAb 10E8 but did not bind to the variable domains of PGT121, suggesting that ADA were primarily directed against the constant regions of the human antibodies. These findings have implications for the development of preclinical studies examining multiple infusions of human bNAbs.

Development of Risk Assessment Index System on HIV infection among young students based on Delphi method

Objective: To develop a Risk Assessment Index System (RAIS) on HIV infection among young students based on Delphi method and to provide individual HIV infection risk assessment, targeted prevention and control measures. Methods: Delphi method was applied to determine the index system and weight of the assessment tool through three rounds of expert consultation and overall consideration of opinions and suggestions from 19 experts. Results: The positivity coefficients of three rounds of expert consultation were 100%. The authority coefficient of experts was between 0.887 and 0.945. The Kendall's W coefficients through first, second and third round specialist consultation was 0.379, 0.329 and 0.248, respectively (all P<0.001). The coefficients of variation in the third round were all less than 0.25, indicating that experts' opinion tend to be consistent and the results are highly reliable. The HIV infection risk assessment index system among young students consisted of 7 first grade indices and 54 second grade indices, of which weight was calculated. Conclusions: The RAIS on HIV infection for young students was initially established based on Delphi method, and could be used in the development of HIV infection risk assessment tools for personalized prevention and intervention among young students. However, the reliability, validity and effect of this assessment index system need to be further evaluated.

Clinical Characteristics of Incident Lymphoma in Malawi before and after Implementation of Universal Anti-Retroviral Therapy

Purpose:In 2016, Malawi implemented a universal test and treat (UTT) policy, expanding eligibility for antiretroviral therapy (ART) to anyone with confirmed HIV infection. Prior to 2016, Malawi restricted ART initiation to HIV-positive individuals with CD4 count ≤500 cells/µL, with WHO staging ≥III who were pregnant or breastfeeding, or who were younger than 5 years old. Here, we assess the impact on distribution of lymphoma presentation and baseline clinical characteristics at Kamuzu Central Hospital, Lilongwe, Malawi.Methods:Participants with newly diagnosed, pathologically confirmed lymphoproliferative disorders were enrolled from 2013 - 2020. We categorized participants as pre-universal ART (pre-UART) if enrolled during 2013-June 2016 or post-universal ART (post-UART) if enrolled during July 2016-2020 and evaluated clinical characteristics.Findings:Of 412 total participants, 156 were pre-UART and 256 were post-UART. The most common diagnoses were diffuse large B-cell lymphoma (DLBCL) (45%), low-grade lymphoma (11%), Burkitt lymphoma (10%), Hodgkin lymphoma (9%), and multicentric Castleman disease (7%) and there was no significant difference in distribution of diagnoses between pre-UART and post-UART periods (Figure 1). HIV prevalence was 50%, mean age 43, and 62% male. Sixty-six percent (48/73) of pre-UART HIV-positive participants knew their HIV status, for median 5 years (IQR 2-8) and 71% (41/58) were on ART for median 4 years (IQR 2-7). Eighty percent (94/117) of post-UART HIV positive participants knew their HIV status (p=0.02), for median 4 years (IQR 2-9) and 84% (89/106) were on ART (p=0.05) for median 4 years (IQR 2-8). HIV was suppressed <1000 copies/mL in 56% (33/59) pre-UART and 71% (73/103) post-UART (p=0.05). Among DLBCL participants, 61% (23/38) of pre-UART HIV-positive participants knew their HIV status, for median 5 years (IQR 2-9), 61% (19/31) were on ART for median 4 years (IQR 2-6). Eighty-two percent (n=51/63) of post-UART DLBCL HIV-positive participants knew their HIV status (p=0.02) for median 5 years (IQR 2-9) and 89% (47/53) were on ART (p < 0.01) for median 5 years (IQR 2-9). Post-UART DLBCL participants had median HIV viral load of 0 log copies/mL (IQR 0-10) compared to pre-UART (6.2; IQR 0-10) (p=0.09). CD4 count, age adjusted-IPI and Ki67 proliferation index were similar for DLBCL patients in the two groups.Interpretation:There were no significant differences in lymphoma subtypes diagnosed or in traditional DLBCL prognostic factors after implementation of universal ART in Malawi. However, HIV was better controlled in the post-UART period and differences in immunological status may have implications for therapy and prognosis. Strengths of this study include a deeply characterized cohort, both clinically and pathologically. As opposed to epidemiological data from the US and Europe, we did not see a major shift in diagnoses over this time period with increasing access to ART. However, possible explanations for the differences include that this is not a epidemiological survey as cancer registration data is not comprehensively collected in Malawi and that the roll out of ART across sub-Saharan Africa has been much more gradual than the abrupt increase in access that was seen in the US and Europe. Therefore, epidemiological chances may also be more gradual. In summary, this is some of the most comprehensive data on lymphoma presentation from sub-Saharan Africa across periods of increasing access to ART and despite improved HIV control among incident lymphoma cases, there was no change in the distribution of diagnoses in this time period. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Factors Contributing to High HIV Prevalence in Majang Zone, Southwest Ethiopia: What Lies Beneath the Tip of the Iceberg?

BackgroundDespite the tremendous efforts made, HIV epidemic has been continuing to be a public health threat and one of the leading causes of death in sub-Saharan African countries. Gambella region is a high prevalence region persistently exhibiting the highest share of HIV cases in Ethiopia. Thus, the objective of this study was to explore factors contributing to high HIV prevalence in the Majang zone of Gambella region, Southwest Ethiopia.MethodsA descriptive qualitative study was conducted in the Majang zone of Gambella region, Southwest Ethiopia from March to May 2019. A heterogeneous purposive sampling technique was employed to recruit key informants and focused group discussion participants. Eighteen key informant interviews and 9 focused group discussions were conducted (N = 90) with health professionals, youth, mothers, and community elders. An interview guide developed through an extensive literature review was used to elicit information from the study participants, and data were collected by the investigators themselves with the help of local guides. Data were audio recorded, transcribed, translated, coded, and analyzed thematically, assisted by Atlas.ti 7.5.16 software. Trustworthiness of the data was ensured through data triangulation, prolonged engagement, member checking, and inquiry audit in which findings were audited and verified by qualitative research experts. Ethical clearance was obtained from the Institutional Review Board of Mizan Tepi University, and written signed informed consent was obtained from all the participants prior to conducting the interviews.ResultsA total of 90 individuals have participated in this study. Several factors appear to underlie the sustained high prevalence of HIV in the study area and were organized into five major themes: 1) government-related factors, 2) community perception towards HIV, 3) substance use, 4) socio-cultural factors, and 5) movement of people.ConclusionLow government attention towards HIV prevention and control activities, low perceived severity of HIV, substance use, socio-cultural factors, and high movement of people appear to inform the understanding of factors contributing to HIV risk in Majang zone. The sociocultural factors include the use of “Tifo Bet” and social support for polygamy. These findings loudly call for the governmental, non-governmental, and private sectors to reconsider and strengthen strategies for the prevention and control of HIV in the study area.

Integrating health services for HIV infection, diabetes and hypertension in sub-Saharan Africa: a cohort study

BackgroundHIV, diabetes and hypertension have a high disease burden in sub-Saharan Africa. Healthcare is organised in separate clinics, which may be inefficient. In a cohort study, we evaluated integrated management...

Antiretroviral therapy for HIV and intrahepatic hepatitis C virus replication.

HIV alters host responses to hepatitis C virus (HCV). However, the impact of antiretroviral therapy (ART) on HCV is rarely understood in relevant tissues and never before within individual hepatocytes. HIV and HCV kinetics were studied before and after ART initiation among 19 HIV/HCV co-infected persons. From five persons with the largest decline in plasma HCV RNA, liver tissues collected before and during ART, when plasma HIV RNA was undetectable, were studied. We used single-cell laser capture microdissection and quantitative PCR to assess intrahepatic HCV. Immunohistochemistry was performed to characterize intrahepatic immune cell populations. Plasma HCV RNA declined by 0.81 (0.52-1.60) log10 IU/ml from a median (range) 7.26 (6.05-7.29) log10 IU/ml and correlated with proportions of HCV-infected hepatocytes (r = 0.89, P = 2 × 10-5), which declined from median (range) of 37% (6-49%) to 23% (0.5-52%) after plasma HIV clearance. Median (range) HCV RNA abundance within cells was unchanged in four of five participants. Liver T-cell abundance unexpectedly decreased, whereas natural killer (NK) and NK T-cell infiltration increased, correlating with changes in proportions of HCV-infected hepatocytes (r = -0.82 and r = -0.73, respectively). Hepatocyte expression of HLA-E, an NK cell restriction marker, correlated with proportions of HCV-infected hepatocytes (r = 0.79). These are the first data to show that ART control of HIV reduces the intrahepatic burden of HCV. Furthermore, our data suggest that HIV affects the pathogenesis of HCV infection by an NK/NK T-cell-mediated mechanism that may involve HLA-E and can be rescued, at least in part, by ART.

HIV serodiscordant and nondisclosure rates among married women living with HIV in a Southern Nigerian region

Objectives: Intimate sexual partners’ disclosure of HIV positive status is vital in the control of HIV/AIDS pandemic globally. The disclosure rates vary from region to region. The aim of this study was to document the prevalence of HIV serodiscordance and partners disclosure rate; and also determine the associated factors among HIV positive married women living in Calabar region of Nigeria. Material and Methods: A cross-sectional survey was conducted among 260 married women, 18 years and above, receiving HIV care at various health institutions in the region. Data were analyzed using SPSS VERSION 23. Their demographic and health profile were presented in simple proportion and percentages while Chi-square test and logistic regression were used to determine the factors influencing patient’s HIV status disclosure with the level of significance set at 0.05. Results: A total of 254 compiled questionnaires were included in the analysis (response rate-97.7%). The serodiscordant rate was 50%. HIV status disclosure to partner was high, 89.4%. The main determinants of HIV status disclosure were good level of education (AOR = 2.2, 95% CI: = 1.75–2.53, P = 0.007) and long duration of ART use (AOR = 3.23, 95% CI = 2.78–4.15, P = 0.001) while women with high discordant rate were more likely to be divorced/separated (P = 0.012, OR = 1.67). Conclusion: Female education is an important factor in HIV control. Disclosure of HIV status is beneficial to the partner as it promotes safe sex practices and increases adherence to ART.

Treatment outcomes among adults with HIV/non-communicable disease multimorbidity attending integrated care clubs in Cape Town, South Africa

BackgroundThe growing burden of the HIV and non-communicable disease (NCD) syndemic in Sub- Saharan Africa has necessitated introduction of integrated models of care in order to leverage existing HIV care infrastructure for NCDs. However, there is paucity of literature on treatment outcomes for multimorbid patients attending integrated care. We describe 12-month treatment outcomes among multimorbid patients attending integrated antiretroviral treatment (ART) and NCD clubs in Cape Town, South Africa.MethodsAs part of an integrated clubs (IC) model pilot implemented in 2016 by the local government at two primary health care clinics in Cape Town, we identified all multimorbid patients who were enrolled for IC for at least 12 months by August 2017. Mean adherence percentages (using proxy of medication collection and attendance of club visits) and optimal disease control (defined as the proportion of participants achieving optimal blood pressure, glycosylated haemoglobin control and HIV viral load suppression where appropriate) were calculated at 12 months before, at the point of IC enrolment and 12 months after IC enrolment. Predictors of NCD control 12 months post IC enrolment were investigated using multivariable logistic regression.ResultsAs of 31 August 2017, 247 HIV-infected patients in total had been enrolled into IC for at least 12 months. Of these, 221 (89.5%) had hypertension, 4 (1.6%) had diabetes mellitus and 22 (8.9%) had both diseases. Adherence was maintained before and after IC enrolment with mean adherence percentages of 92.2% and 94.2% respectively. HIV viral suppression rates were 98.6%, 99.5% and 99.4% at the three time points respectively. Retention in care was high with 6.9% lost to follow up at 12 months post IC enrolment. Across the 3 time-points, optimal blood pressure control was achieved in 43.1%, 58.9% and 49.4% of participants while optimal glycaemic control was achieved in 47.4%, 87.5% and 53.3% of participants with diabetes respectively. Multivariable logistic analyses showed no independent variables significantly associated with NCD control.ConclusionMultimorbid adults living with HIV achieved high levels of HIV control in integrated HIV and NCD clubs. However, intensified interventions are needed to maintain NCD control in the long term.

Comparative analysis of the serum microbiome of HIV infected individuals

HIV infects the CD4 cells which marks the suppression of our immune system. DNA from serum of healthy, treated and untreated HIV infected individuals was extracted. The DNA was subjected to 16S metagenomic sequencing and analyzed using QIIME2 pipeline. 16S sequencing analysis showed serum microbiome was dominated by Firmicutes, Proteobacteria, Bacteroidota and Actinobacteria. Treated HIV infection showed highest abundance of Firmicutes (66.40%) significantly higher than untreated HIV infection (35.88%) and control (41.89%). Bacilli was most abundant class in treated (63.59%) and second most abundant in untreated (34.53%) while control group showed highest abundance of class Gamma-proteobacteria (45.86%). Untreated HIV infection group showed Enterococcus (10.72%) and Streptococcus (6.599%) as the most abundant species. Untreated HIV infection showed significantly higher (p = 0.0039) species richness than treated and control groups. An altered serum microbiome of treated HIV infection and higher microbial abundance in serum of untreated HIV infection was observed.

HIV stigma in the teaching hospitals in Sana\u2019a, Yemen: a conflict and low-resource setting

BackgroundHIV stigma undermines a person’s wellbeing and quality of life and hinders HIV control efforts. This study examined the extent and drivers of HIV stigma in the teaching hospitals in Sana’a City, Yemen. The country has low HIV prevalence (4000 (2000-11,000) per 100,000) and limited HIV control funds, worsened by a long conflict and an economic crisis.MethodsWe conducted a cross-sectional study of 320 Yemeni health professionals in all the four teaching hospitals in Sana’a City. Data were collected anonymously, using an adapted self-completed Arabic version of the Health Policy Project HIV Stigma tool. The questionnaire covered the respondents’ background, the stigmatising practices, and potential personal and professional drivers of stigma.ResultsThe majority of the participants were: females (68%), 20–39 years old (85%), nurses (84%), and holding a nursing diploma (69%) or a bachelor’s degree (27%). None of the hospitals had institutional policies against HIV stigma, and 93% of the participants believed the current infection control measures were inadequate. Less than half of the participants provided care for people living with HIV (PLHIV) (45%), had received HIV training (33%), and were confident that their HIV knowledge was adequate (23%). The majority indicated a preference to test patients for HIV prior to surgical procedures (77%) and disclose positive HIV results to others (99%) without prior knowledge or consent. All the participants had exhibited a form of HIV-related stigmatization, such as avoiding physical contact with PLHIV (87%) or wearing gloves throughout the consultation (96.5%). These practices were significantly correlated with the fear of infection, high perceived risk of infection, and poor work environment (p < 0.05).ConclusionPLHIV face widespread stigmatizing behaviour in the teaching hospitals in Sana’a City, consistent with the higher level of stigma in low HIV prevalence countries and its links to the fear of infection, poor HIV knowledge, and limited funding for HIV control. Stigma reduction interventions are required at institutional and individual levels. In addition, anti-discrimination policies and structural adjustments are needed, in combination with training on HIV and universal precautions, and action to tackle negative attitudes towards PLHIV and key populations.

Distinct antibody profiles in HLA-B∗57+, HLA-B∗57- HIV controllers and chronic progressors.

Objective:Spontaneous control of HIV replication without treatment in HIV-1 controllers (HICs) was associated with the development of an efficient T-cell response. In addition, increasing data suggest that the humoral response participates in viral clearance.Design:In-depth characterization of Ab response in HICs may help to define new parameters associated with this control.Methods:We assessed the levels of total and HIV-specific IgA and IgG subtypes induction and their functional potencies – that is, neutralization, phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), according to the individual's major histocompatibility complex class I (HLA)-B∗57 status, and compared it with nontreated chronic progressors.Results:We found that despite an undetectable viral load, HICs displayed HIV-specific IgG levels similar to those of chronic progressors. Interestingly, our compelling multifunctional analysis demonstrates that the functional Ab profile, by itself, allowed to discriminate HLA-B∗57+ HICs from HLA-B∗57− HICs and chronic progressors.Conclusion:These results show that HICs display a particular HIV-specific antibody (Ab) profile that may participate in HIV control and emphasize the relevance of multifunctional Ab response analysis in future Ab-driven vaccine studies.

Evolution of Serum Acute-Phase Glycoproteins Assessed by 1H-NMR in HIV Elite Controllers.

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) who maintain undetectable viral loads (VLs) despite not being on antiretroviral therapy (ART). However, this phenotype is heterogeneous, with some of these subjects losing virological control over time. In this longitudinal retrospective study, serum acute-phase glycoprotein profile assessed by proton nuclear magnetic resonance (1H-NMR) was determined in 11 transient controllers (TCs) who spontaneously lost virological control and 11 persistent controllers (PCs) who persistently maintained virological control over time. Both PCs and TCs showed similar acute-phase glycoprotein profiles, even when TCs lost the virological control (GlycB, p = 0.824 and GlycA, p = 0.710), and the serum acute-phase glycoprotein signature in PCs did not differ from that in HIV-negative subjects (GlycB, p = 0.151 and GlycA, p = 0.243). Differences in serum glycoproteins A and B were significant only in ECs compared to HIV-typical progressors (TPs) with < 100 CD4+ T-cells (p < 0.001). 1H-NMR acute-phase glycoprotein profile does not distinguish TCs form PCs before the loss of viral control. ECs maintain a low-grade inflammatory state compared to TPs. PCs revealed a closer serum signature to HIV-negative subjects, reaffirming this phenotype as a closer model of functional control of HIV.

Exosome-mediated stable epigenetic repression of HIV-1

Human Immunodeficiency Virus (HIV-1) produces a persistent latent infection. Control of HIV-1 using combination antiretroviral therapy (cART) comes at the cost of life-shortening side effects and development of drug-resistant HIV-1. An ideal and safer therapy should be deliverable in vivo and target the stable epigenetic repression of the virus, inducing a stable “block and lock” of virus expression. Towards this goal, we developed an HIV-1 promoter-targeting Zinc Finger Protein (ZFP-362) fused to active domains of DNA methyltransferase 3 A to induce long-term stable epigenetic repression of HIV-1. Cells were engineered to produce exosomes packaged with RNAs encoding this HIV-1 repressor protein. We find here that the repressor loaded anti-HIV-1 exosomes suppress virus expression and that this suppression is mechanistically driven by DNA methylation of HIV-1 in humanized NSG mouse models. The observations presented here pave the way for an exosome-mediated systemic delivery platform of therapeutic cargo to epigenetically repress HIV-1 infection.

Collaboration of a Detrimental HLA-B*35:01 Allele with HLA-A*24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes.

ABSTRACTAlthough mutant-specific T cells are elicited in some individuals infected with HIV-1 mutant viruses, the detailed characteristics of these T cells remain unknown. A recent study showed that the accumulation of strains expressing Nef135F, which were selected by HLA-A*24:02-restricted T cells, was associated with poor outcomes in individuals with the detrimental HLA-B*35:01 allele and that HLA-B*35:01-restricted NefYF9 (Nef135-143)-specific T cells failed to recognize target cells infected with Nef135F mutant viruses. Here, we investigated HLA-B*35:01-restricted T cells specific for the NefFF9 epitope incorporating the Nef135F mutation. Longitudinal T-cell receptor (TCR) clonotype analysis demonstrated that 3 types of HLA-B*35:01-restricted T cells (wild-type [WT] specific, mutant specific, and cross-reactive) with different T cell repertoires were elicited during the clinical course. HLA-B*35:01+ individuals possessing wild-type-specific T cells had a significantly lower plasma viral load (pVL) than those with mutant-specific and/or cross-reactive T cells, even though the latter T cells effectively recognized the mutant virus-infected cells. These results suggest that mutant-specific and cross-reactive T cells could only partially suppress HIV-1 replication in vivo. An ex vivo analysis of the T cells showed higher expression of PD-1 on cross-reactive T cells and lower expression of CD160/2B4 on the mutant-specific T cells than other T cells, implying that these inhibitory and stimulatory molecules are key to the reduced function of these T cells. In the present study, we demonstrate that mutant-specific and cross-reactive T cells do not contribute to the suppression of HIV-1 replication in HIV-1-infected individuals, even though they have the capacity to recognize mutant virus-infected cells. Thus, the collaboration of HLA-A*24:02 with the detrimental allele HLA-B*35:01 resulted in the coevolution of HIV-1 alongside virus-specific T cells, leading to poorer clinical outcomes.IMPORTANCE HIV-1 escape mutations are selected under pressure from HIV-1-specific CD8+ T cells. Accumulation of these mutations in circulating viruses impairs the control of HIV-1 by HIV-1-specific T cells. Although it is known that HIV-1-specific T cells recognizing mutant virus were elicited in some individuals infected with a mutant virus, the role of these T cells remains unclear. Accumulation of phenylalanine at HIV-1 Nef135 (Nef135F), which is selected by HLA-A*24:02-restricted T cells, led to poor clinical outcome in individuals carrying the detrimental HLA-B*35:01 allele. In the present study, we found that HLA-B*35:01-restricted mutant-specific and cross-reactive T cells were elicited in HLA-B*35:01+ individuals infected with the Nef135F mutant virus. These T cells could not effectively suppress HIV-1 replication in vivo even though they could recognize mutant virus-infected cells in vitro. Mutant-specific and cross-reactive T cells expressed lower levels of stimulatory molecules and higher levels of inhibitory molecules, respectively, suggesting a potential mechanism whereby these T cells fail to suppress HIV-1 replication in HIV-1-infected individuals.

HIV Broadly Neutralizing Antibodies Expressed as IgG3 Preserve Neutralization Potency and Show Improved Fc Effector Function.

The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality.

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+ Tcells 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 Tcell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ Tcells 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+ Tcells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ Tcells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

Reducing stigma, depression, and anxiety in people with HIV through a cognitive behavioral therapy group

A number of people with HIV participated in a 48-hour cognitive behavioral group intervention, divided into four monthly workshops. Twenty-six participants started the program and 18 completed it and responded at the four-month follow-up. After treatment, significant improvement was achieved in declared stigma, internalized stigma, depression, and state anxiety. All these improvements were maintained at the follow-up measurement four months later, with trait anxiety also improving in this last measure. Participants’ results were compared with an HIV control group. Twenty-four respondents completed the first test battery and 16 completed the last. The evolution of this group was assessed, as well as the differences between both groups at three time points: pre-intervention, post-intervention, and follow-up. Intragroup and inter-group comparisons were examined with the Student t-tests for related samples and for independent samples respectively. In addition, the effect size was calculated for each comparison. The results support the efficacy of the group intervention presented.

Incorporating the Cluster A and V1V2 Targets into a Minimal Structural Unit of the HIV-1 Envelope to Elicit a Cross-Clade Response with Potent Fc-Effector Functions.

The generation of a potent vaccine for the prevention and/or control of HIV-1 has been unsuccessful to date, despite decades of research. Existing evidence from both infected individuals and clinical trials support a role for non-neutralizing or weakly neutralizing antibodies with potent Fc-effector functions in the prevention and control of HIV-1 infection. Vaccination strategies that induce such antibodies have proven partially successful in preventing HIV-1 infection. This is largely thought to be due to the polyclonal response that is induced in a vaccine setting, as opposed to the infusion of a single therapeutic antibody, which is capable of diverse Fc-effector functions and targets multiple but highly conserved epitopes. Here, we build on the success of our inner domain antigen, ID2, which incorporates conformational CD4-inducible (CD4i) epitopes of constant region 1 and 2 (C1C2 or Cluster A), in the absence of neutralizing antibody epitopes, into a minimal structural unit of gp120. ID2 has been shown to induce Cluster A-specific antibodies in a BALB/c mouse model with Fc-effector functions against CD4i targets. In order to generate an immunogen that incorporates both epitope targets implicated in the protective Fc-effector functions of antibodies from the only partially successful human vaccine trial, RV144, we incorporated the V1V2 domain into our ID2 antigen generating ID2-V1V2, which we used to immunize in combination with ID2. Immunized BALB/c mice generated both Cluster A- and V1V2-specific antibodies, which synergized to significantly improve the Fc-mediated effector functions compared to mice immunized with ID2 alone. The sera were able to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). We therefore conclude that ID2-V1V2 + ID2 represents a promising vaccine immunogen candidate for the induction of antibodies with optimal Fc-mediated effector functions against HIV-1.

Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

Levels of mother-to-child HIV transmission knowledge and associated factors among reproductive-age women in Ethiopia: Analysis of 2016 Ethiopian Demographic and Health Survey Data.

The world community has committed to eliminating the mother-to-child transmission of human immunodeficiency virus. Even though different studies have been done in Ethiopia, to the knowledge of the investigators, the Ethiopian women's level of knowledge on the mother-to-child transmission of human immunodeficiency virus is not well studied and the existing evidence is inconclusive. The current study is aimed to study the Ethiopian women's level of knowledge on the mother-to-child transmission of human immunodeficiency virus and its associated factors using the 2016 Ethiopian Demographic and Health Survey Data. Data of 15,683 women were extracted from the 2016 Ethiopia Demographic and Health Survey. Descriptive statistics and multilevel ordinal logistic regression were respectively used for the descriptive and analytical studies. 41.1% [95% CI: 39.5%, 42.7%] of the Ethiopian reproductive-age women have adequate knowledge of the mother-to-child transmission of human immunodeficiency virus. 77%, 84% and 87.8% of the women respectively know that human immunodeficiency virus can be transmitted during pregnancy, delivery, and breastfeeding. There are wider regional variations in the women's level of knowledge of the mother-to-child transmission of human immunodeficiency virus. Being an urban resident, having better educational status, being from a wealthy household, owning of mobile phone, frequency of listening to the radio, frequency of watching television, and being visited with field workers were significantly associated with having adequate knowledge of the mother-to-child transmission of human immunodeficiency virus. Despite all collective measures put in a place by different stakeholders to prevent the mother-to-child transmission of HIV in Ethiopia, a large proportion of the Ethiopian women do not know about the mother-to-child transmission of the disease. Stakeholders working on HIV prevention and control should give due emphasis to promoting mobile phone technology and other media like radio and television by giving due focus to rural residents and poor women to promote the current low level of the knowledge. Emphasis should also be given to the information, education, and communication of the mother-to-child transmission of the disease through community-based educations.