Background. There are limited data on kidney replacement therapy (KRT) allocation and outcomes in patients in kidney failure (KF) who access public healthcare in South Africa. Methods. This retrospective cohort study included patients referred for KRT at the time of KF diagnosis. Incident KF cases were identified between 2012 and 2020, followed from referral until death, kidney transplantation, or continued waitlisting at study end (December 31, 2023). Descriptive analyses and comparisons were performed between KRT allocation and outcomes. Time-to-event analyses employed competing risk models to estimate cumulative incidence functions, whereas Kaplan-Meier methods were applied to calculate survival probabilities. Results. Overall, 761 patients were referred with KF, of which 598 (79%) were untreated and presumed to have died. Untreated patients were either not considered at referral (n = 432), or not accepted at KRT committee meeting (n = 175) because of policy-driven factors. Of those presented to the KRT committee (n = 338), 48% (n = 163) were accepted onto the dialysis program and waitlisted for transplantation. Accepted patients were younger and had greater medical stability and socioeconomic circumstances compared with non-accepted patients. Only 21% (n = 34) of patients initiated on dialysis were transplanted. At 5 y post-KRT initiation, there was a greater probability of dying on the waitlist compared with receiving a transplant (cumulative incidence function 35% [95% CI, 27-42] versus 18% [95% CI, 13-25]), and post-transplantation survival was significantly greater than pre-transplant survival (100% versus 61% [95% CI, 53-69]). Conclusions. Our study findings align with the challenges of providing dialysis and transplantation in a lower- to middle-income setting where patients were most often precluded from KRT because of poorly controlled comorbidities or a lack of unit capacity. There was a clear survival advantage in patients who were transplanted over those who remained on dialysis; however, transplant services remain limited.

Human Immunodeficiency Virus type 1 (HIV-1) is responsible for the global HIV/AIDS epidemic and the establishment of an integrated HIV-1 reservoir remains the primary obstacle to cure. Upon therapy interruption, reactivation of the persistent HIV-1 reservoir propagates viral rebound and mediates continued immunological decline. While furthering understanding of the HIV-1 reservoir is essential for HIV-1 cure, commonly used sequencing strategies are often limited by the reliance on short-read sequencing across separate assays to determine integration sites and proviral integrity - something that does not always adequately resolve complex human genomic repeats or low complexity regions. Simultaneous identification of proviral integration sites and proviral integrity at the single molecule level would enable HIV-1 reservoir characterization with minimal imputation or bioinformatic reconstruction. Here we present HIV Single Molecule Real Time Capture (HIV SMRTcap), a novel molecular and computational pipeline that directly and simultaneously identifies HIV-1 integration sites, defines proviral integrity, and characterizes clonal expansion of HIV-1 provirus-containing cells with single molecule resolution. In combination with long-read, single-molecule, real-time (SMRT) sequencing and custom analytic pipelines, HIV SMRTcap enables a highly comprehensive characterization of HIV-1 reservoirs. Moreover, we demonstrate here that HIV SMRTcap performs robustly across the major global subtypes (HIV-1 subtype A, B, C, D and A/D recombinant viruses), and can use both cell- and tissue-derived inputs, including samples from antiretroviral therapy (ART) treated individuals with undetectable viral loads. Our results demonstrate that HIV SMRTcap serves as a comprehensive, robust method for unbiased HIV-1 reservoir characterization. Used alone, or in combination with single-cell based methods, HIV SMRTcap will enable novel exploration of viral reservoirs across subtypes and in tissue-specific compartments, providing critical information needed to inform HIV-1 cure.

People with HIV-1 have higher risk for rejection after kidney transplantation but the mechanism is poorly understood. As HIV latency promotes immune dysregulation and chronic inflammation, we evaluated whether the size of the HIV latent viral reservoir (LVR) at baseline and through 52-weeks is associated with rejection in kidney transplant recipients with HIV from donors with and without HIV. Using the intact proviral DNA assay, we found no differences in the LVR between those who experienced rejection (n = 14) versus those who did not (N = 55) regardless of donor HIV status. These data support the feasibility of HIV+ to HIV+ organ transplantation. Clinical Trials Registration. NCT03500315.

BACKGROUND:Estimating HIV viremic time helps better understand reservoir dynamics and inform cure trials. Traditional approaches rely on serological assays or CD4 counts, which can lack precision. Sequence-based estimates using pretreatment RNA diversity help address this, but are limited by immediate ART initiation. METHODS:We developed Bayesian models to predict viremic time from diversity in HIV reservoir sequences in 2 cohorts from Uganda and Sweden. We computed 6 diversity metrics for gp41, RT, and matrix p17. We fitted 36 models per region using slope-fitting and weighting strategies and evaluated predictive accuracy and diagnostics. We validated top models in participants with diagnosis dates but unknown seroconversion dates. RESULTS:Reservoir diversity increased with viremic time. Models using unique RT and gp41 sequences performed well; combining regions improved predictions, especially using nucleotide diversity and mean TN93 distances. In validation, estimates and credible intervals that aligned with diagnosis dates; and log-transformed sequence count weights increased precision. Models using matrix p17, complex metrics, or identical sequences showed weaker performance. CONCLUSIONS:We present a new Bayesian approach to estimate HIV viremic time from reservoir sequences. This approach works across subtypes and chronic infection, uses simple diversity metrics, and may support research on reservoir dynamics and cure.

We analyzed perinatal transmission in a pre-antiretroviral therapy Ugandan cohort by maternal human immunodeficiency virus type 1 subtype and infant sex in 131 mother-child pairs. Among all children, if the mother was infected with subtype A there was a nearly 3-fold increased risk of perinatal transmission compared with subtype D (risk ratio [RR], 2.96 [95% confidence interval (CI), 1.46-6.01]; P = .008). When stratifying infants by both sex and maternal subtype, significantly more female (56.3% [9 of 16]) than male (9.1% [1 of 11]) infants born to mothers with subtype A were infected (RR, 6.19 [95% CI, .91-42.12]; P = .02). In contrast, among infants born to mothers with subtype D, transmission rates were comparable across sex (RR, 1.59 [95% CI, .57-4.41]; P = .39).

BACKGROUND Transplanting kidneys from donors with HIV to recipients with HIV has become standard clinical practice. However, donors with HIV may have higher prevalence of viral and bacterial infections and autoimmunity that could increase allograft rejection in recipients. METHODS We included deceased kidney donors (60 with HIV and 41 without HIV) who participated in a multicenter prospective study of HIV kidney transplantation between April 2018 and September 2021. Using phage immunoprecipitation sequencing, we compared the human antibody repertoire (allergens, autoantibodies, viruses, and bacterial toxins) between donors with and without HIV and evaluated their association with recipient allograft rejection. Moderated t tests were used to assess reactivity and a multivariate logistic regression model adjusted for donor sex and kidney donor profile index assessed the association between donor adenovirus reactivity and recipient allograft rejection. RESULTS Compared with donors without HIV, donors with HIV had lower BMI and were more likely to be African American. The median number of positive autoantibodies was marginally higher among donors with HIV (499 [IQR, 357, 579]) compared with that of donors without HIV (395 [IQR, 256, 538], P = 0.058). Donors with HIV additionally had significantly higher antibody reactivity to Epstein-Barr virus and cytomegalovirus ( q < 0.05). Among all donors with and without HIV, antibodies against adenovirus were significantly associated with increased rejection among recipients, including after adjusting for false discovery ( q < 0.05) and also adjusting for demographic factors using multivariable logistic regression (odds ratio = 4.97; 95% CI = 1.89–13.61). CONCLUSION The presence of antibodies against adenovirus infection in kidney donors with HIV may be associated with allograft rejection. TRIAL REGISTRATION ClinicalTrials.gov NCT03500315. FUNDING US NIH.

BACKGROUND:The cervicovaginal microbiome may affect HIV-1 susceptibility and can in turn influence the prevalence and clinical course of HIV-1 and other sexually transmitted diseases. As the determinants, immunological correlates and clinical effects of the dysbiosis observed in women living with HIV-1 (WWH) remain elusive, we evaluated the vaginal immunologic milieu, cervicovaginal microbiome and prevalence of human papillomaviruses (HPV) in antiretroviral-naïve WWH over their first year of antiretroviral therapy (ART). METHODS:83 ART-naïve Ugandan WWH were enrolled in a longitudinal observational trial. Clinical evaluation and sampling of cervicovaginal secretions and plasma were performed at 0, 8, 24 and 52 weeks post-ART initiation. Amplification of the 16S-rRNA gene V3-V4 region was used to determine the cervicovaginal microbiome. A multiplex bead-array assay was used to quantify the concentration of biomarkers while a PCR-based hybridization assay was utilized for HPV detection and genotyping. RESULTS:Gardnerella was the most abundant genus with a median relative abundance of 35% before ART maintaining a high prevalence throughout the study. Vaginal bacterial diversity did not change after ART, although the relative abundance of some genera, including the bacterial-vaginosis-associated bacteria Peptostreptococcus and Prevotella, decreased compared to baseline. Inflammatory biomarkers remained elevated in the cervicovaginal compartment despite prompt decreases in plasma.The prevalence of high and low-risk HPV types remained stable despite ART. CONCLUSIONS:Suppression of HIV-1 replication is not sufficient to revert dysbiotic changes, proinflammatory immunological milieu and persistent HPV infections. Exploration of targeted strategies to restore cervicovaginal mucosal immunological functions in WWH is warranted.

Background: Apolipoprotein L1 (APOL1) G1 and G2 kidney risk variants (APOL1 KRV) are strongly associated with chronic kidney disease (CKD) in populations of African ancestry, yet evidence from sub-Saharan Africa remains limited, particularly regarding infectious modifiers of APOL1-associated risk. We investigated APOL1 KRV prevalence and whether HIV modifies risk associated with monoallelic and biallelic carriage in a South African CKD cohort. Methods: We conducted a cross-sectional study of 493 adults with CKD in Gqeberha, South Africa. APOL1 G1, G2, and p.N264K modifier 1 (M1) variants were identified using Sanger sequencing. Multivariable logistic regression evaluated associations with advanced CKD, including an HIV × APOL1 interaction term. Findings: At least one APOL1 risk allele was present in 32.5% of participants while 7.1% carried two risk alleles. HIV was present in 16.6% and prior tuberculosis (TB) in 22.1%. Neither APOL1 carriage nor HIV infection alone was associated with advanced CKD. However, participants with both HIV and ≥1 APOL1 risk allele had substantially higher odds of advanced CKD (adjusted odds ratio 4.7, 95% CI 1.07-20.64). This association persisted in analyses restricted to monoallelic carriers and in ancestry-restricted sensitivity analyses. Interpretation: APOL1 KRV are common in this South African CKD cohort and interact with HIV infection to substantially increase the risk of advanced CKD, even among monoallelic carriers. These findings support an exposure-dependent model of APOL1 kidney disease and highlight the importance of integrating genetic and infectious risk factors in African CKD populations.

Background. BK virus-associated nephropathy (BKVN) is a viral complication after kidney transplantation and an important cause of graft dysfunction and loss. Its impact on HIV-positive kidney transplant recipients (KTRs), who are at increased risk for opportunistic infections, remains poorly understood. Methods. This single-center case series in South Africa describes BKVN incidence and outcomes in HIV-positive KTRs who received kidneys from HIV-positive donors between 2008 and 2025. A screening protocol and schedule were implemented in 2021, and BKVN was classified as possible, probable, or presumptive according to The Second International Consensus Guidelines. Results. Over the study period, there were 63 KTRs and 34 donors; 2 recipients with primary graft failure were excluded. The remaining 61 recipients had a median age of 40 y, 54% were male, and 93% were of Black African ethnicity. Median CD4 count at transplantation was 439 cells/mm3, and all KTRs had suppressed HIV viral load on antiretroviral therapy. HIV-associated nephropathy was the most common cause of end-stage kidney disease. Hypertension was prevalent (89%), and one-third had a history of treated tuberculosis. All patients received antithymocyte globulin induction at transplant. Seventeen recipients had no BKVN screening data, 36 maintained negative BK viral loads, while 8 developed BK polyomavirus viremia and/or viruria. Of these, 2 (3%) had polymerase chain reaction-confirmed viremia, and 6 (10%) met criteria for possible (n = 1), probable (n = 2), or presumptive BKVN (n = 3). BK polyomavirus viremia and/or viruria occurred either within 6 mo or between 1 and 2 y posttransplant. Management consisted of reducing immunosuppression. Possible and probable cases (5%) maintained functioning grafts. All 3 (5%) presumptive cases had biopsy-proven disease, with one resulting in graft loss (1.6%). Conclusions. Despite limited resources and delayed routine screening, the BKVN incidence was low (5%), and most affected recipients achieved viral control and preserved graft function.

HIV-1 Nef mediates immune evasion and viral pathogenesis in part through the downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While the Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in the persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct nef genes (n = 82) with varying estimated times of reservoir entry were selected from viral outgrowth variants stimulated from the reservoir of South African women living with HIV who initiated ART during chronic infection (n = 16). These nef genes were synthesized and used in a pseudovirus infection assay that measures CD4 and MHC-I downregulation via flow cytometry. Downregulation measures were compared to the size of the replication-competent viral reservoir (RC-VR), estimated by quantitative viral outgrowth assay at 5 years after treatment initiation, as well as proviral survival time. Maximum Nef-mediated MHC-I downregulation was significantly associated with RC-VR size (P = 0.034), but this association was not observed for CD4 downregulation. Conversely, we did not find a consistent association between intraparticipant MHC-I or CD4 downregulation and the variant timing of entry into the reservoir. These data support a role for Nef-mediated MHC-I downregulation in determining RC-VR size, but more work is needed to determine Nef's role in the survival of individual viral variants over time.IMPORTANCERational design of HIV cure interventions requires an understanding of the viral determinants of reservoir dynamics. For an equitable cure, it needs to be broadly applicable. While African women bear the greatest burden of HIV globally, most cure research has focused on men in the global North. Our study aims to elucidate viral determinants of HIV persistence in South African women on antiretroviral therapy. We hypothesized that the HIV protein Nef subverts immune clearance of infected cells by downregulating surface levels of two cellular proteins, CD4 and MHC-I. We compared this downregulation capacity with reservoir size and variant survival in the reservoir. We found a positive association between an individual's reservoir size and MHC-I downregulation, but there was little evidence for a survival benefit with stronger MHC-I reduction. These data support earlier work and suggest that Nef's interaction with MHC-I may be a target to restrict the latent reservoir in cure strategies.

BACKGROUND:Lower allograft survival has been demonstrated in kidney transplant recipients without HIV whose donors have 2 apolipoprotein L1 ( APOL1 ) renal risk variants (RRVs). The effects of APOL1 RRV on kidney transplant outcomes in people with HIV have not been fully assessed. METHODS:Genomic DNA was analyzed for APOL1 RRV genotype using a probe-based assay in HIV-positive kidney transplant recipients (R + ) and their respective HIV-negative (D - ) or HIV-positive (D + ) kidney donors participating in HIV transplantation studies in South Africa (SA) and the United States (US). Allograft outcomes (time to first rejection, HIV-associated nephropathy, graft failure, or death) were compared by both donor and recipient RRV status. RESULTS:Genomic DNA was available for 21 donors with HIV and 38 HIV D + /R + recipients in the SA cohort, and 57 donors (40 D + and 17 D - ) and 119 recipients (49 HIV D + /R + and 70 D - /R + ) in the US cohort. Recipient outcomes were not associated with recipient APOL1 genotype. However, recipients whose donor carried 1 versus 0 APOL1 RRV were significantly more likely to experience a negative composite outcome ( P  < 0.02 for both cohorts independently), which led to an adjusted hazard ratio of a poor composite outcome of 2.9 (95% confidence interval, 1.1 to 7.4) and 10.1 (95% confidence interval, 2.4 to 42.7) in the SA and US cohorts, respectively. CONCLUSIONS:In two independent cohorts, the presence of 1 APOL1 RRV in a donor kidney led to significantly worse posttransplant outcomes. Further research into the interaction between the allograft environment and donor APOL1 genotype in people with HIV is required.

[This corrects the article DOI: 10.1371/journal.pgph.0003554.].

INTRODUCTION:Autoantibodies (AAbs) directed against interferon alpha (aIFNα), nuclear antigens (ANAs), anti-cardiolipin (aCL), and anti-beta 2 glycoprotein 1 (aβ2GP1), have been demonstrated to significantly correlate with the severity of acute Coronavirus Disease 2019 (COVID-19). However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces these AAbs and whether they are associated with long COVID remains unclear. METHODS:The potential induction of aIFNα, ANAs, aCL, and aβ2GP1 by SARS-CoV-2 was assessed by measuring these AAbs in 224 pre- and post-infection paired serum samples from the Johns Hopkins Hospital Emergency Department (JHHED). The relationship between these AAbs and long COVID was assessed using 60 serum samples from participants in the Outpatient SARS-CoV-2 Mild and Asymptomatic Infection Response and Transmission study. RESULTS:We found no evidence that these AAbs were induced in the JHHED cohort and no significant difference in their prevalence between patients with (n = 30) and without (n = 30) long COVID in the OutSMART cohort. CONCLUSION:These findings do not support the hypotheses that SARS-CoV-2 induces these AAbs or that they are related to long COVID.

People living with HIV can acquire secondary infections through a process called superinfection, giving rise to simultaneous infection with genetically distinct variants (multiple infection). Multiple infection provides the necessary conditions for the generation of novel recombinant forms of HIV and may worsen clinical outcomes and increase the rate of transmission to HIV seronegative sexual partners. To date, studies of HIV multiple infection have relied on insensitive bulk-sequencing, labor intensive single genome amplification protocols, or deep-sequencing of short genome regions. Here, we identified multiple infections in whole-genome or near whole-genome HIV RNA deep-sequence data generated from plasma samples of 2,029 people living with viremic HIV who participated in the population-based Rakai Community Cohort Study (RCCS). We estimated individual- and population-level probabilities of being multiply infected and assessed epidemiological risk factors using the novel Bayesian deep-phylogenetic multiple infection model (deep - phyloMI) which accounts for bias due to partial sequencing success and false-negative and false-positive detection rates. We estimated that between 2010 and 2020, 4.09% (95% highest posterior density interval (HPD) 2.95%-5.45%) of RCCS participants with viremic HIV multiple infection at time of sampling. Participants living in high-HIV prevalence communities along Lake Victoria were 2.33-fold (95% HPD 1.3-3.7) more likely to harbor a multiple infection compared to individuals in lower prevalence neighboring communities. This work introduces a high-throughput surveillance framework for identifying people with multiple HIV infections and quantifying population-level prevalence and risk factors of multiple infection for clinical and epidemiological investigations.

Kidney transplantation from donors with HIV has recently become standard clinical practice, but the plasma inflammatory profile is not well characterized. Thirty-two cytokines and chemokines were evaluated among donors with HIV (n = 63) and without HIV (n = 41). Wilcoxon rank sum test was used to compare cytokines between groups. Donors with and without HIV were generally similar in terms of characteristics, except those with HIV had a non-significantly lower kidney donor profile index, reflecting better graft survival, creatinine, and body mass index. Most cytokine and chemokine levels were similar between groups. However, median IL-8 levels were higher (p < 0.0015) in donors without HIV (32.6 pg/mL, IQR = 13.8-394.9) compared to donors with HIV (15.1 pg/mL, IQR = 8.4-35.5). There were no significant correlations between cytokine and chemokine concentrations and CD4 counts or HIV viral load. In summary, inflammatory profiles were similar or lower among donors with HIV compared to donors without HIV supporting the safety of this emerging kidney transplantation practice.

Human papillomavirus (HPV) is a highly prevalent sexually transmitted infection, yet data on HPV dynamics in African male populations remain limited. We conducted a prospective study of 300 human immunodeficiency virus-negative, sexually active Ugandan men enrolled at circumcision and followed every 6 weeks for 6 months. Penile swabs were collected by clinical staff, and HPV DNA was detected using the Roche polymerase chain reaction-based linear array assay at six time points. We estimated both point and cumulative prevalence of any and high-risk HPV, and assessed empirical and bootstrapped absolute and relative differences to quantify bias from relying solely on baseline testing. The baseline prevalence of any HPV was 49.7%, increasing to 66.0% when cumulative results were considered. Among 27 men with swabs with amplifiable viral or cellular DNA at all six visits, 100% tested positive at least once. HPV detection was often transient: only 6.1% of men with any HPV were consistently positive at all visits. Men who were ever HPV positive reported a younger age at first sex and more sexual partners. Single-timepoint testing significantly underestimated HPV prevalence, with relative biases of 24.7% for any HPV and 40.3% for high-risk HPV. Bootstrap analyses showed that reducing absolute bias to below 5% required two visits for any HPV and three for high-risk HPV, whereas achieving relative bias below 5% required three and five visits, respectively. The results remained consistent in sensitivity analyses that excluded pre-circumcision visits. These findings highlight the limitations of cross-sectional HPV testing and emphasize the importance of repeated sampling for accurate surveillance and vaccine impact assessments in male populations.

OBJECTIVE:Autoantibodies (AAbs) to interferon alpha, nuclear antigens, cardiolipin, and beta 2 glycoprotein 1, have been associated with COVID-19 severity. Despite relatively low COVID-19 morbidity and mortality in East and Central Africa, AAb prevalence in these populations remain understudied. METHODS:We evaluated AAb seroprevalence in 155 Ugandans, aged 40-50, using paired samples collected before and after the onset of the COVID-19 pandemic. Among these, 117 had serological evidence of SARS-CoV-2 infection, and 38 did not. To assess the effect of SARS-CoV-2 infection on AAb prevalence, we: 1) longitudinally compared AAb prevalence before and after evidence of infection, and 2) cross-sectionally compared AAb prevalence between those with and without infection evidence at both timepoints. Associations between AAbs and health characteristics were also explored. RESULTS:There was no difference in AAb prevalence between individuals with and without evidence of infection, nor any longitudinal change after evidence of infection. However, we observed a higher-than-expected prevalence anti-beta 2 glycoprotein 1. Additionally, anti-cardiolipin was significantly associated with reported hypertension. CONCLUSIONS:Our findings contribute to the limited literature on AAb prevalence in East Africa and suggest that SARS-CoV-2 does not induce these AAbs.