AIDS research and human retroviruses最新文献

We evaluated HIV DNA levels in individuals who received long-acting cabotegravir (CAB-LA) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis in the HPTN 083 and 084 trials and had HIV DNA testing performed to help determine HIV status. HIV DNA testing was performed using peripheral blood mononuclear cell (PBMC) samples collected after a reactive HIV test was obtained at a study site. DNA was quantified using droplet digital PCR (lower limit of detection [LLOD]: 4.09 copies/million PBMCs). Final HIV status and the timing of the first HIV-positive visit were determined by an independent adjudication committee based on HIV test results from real-time site testing and retrospective testing at a centralized laboratory. HIV DNA testing was performed for 133 participants [21 HIV-positive (7 CAB-LA arm, 14 TDF/FTC arm) and 112 HIV-negative; 1-6 tests/person]. For persons with HIV, the time between the first HIV-positive visit and collection of the first sample for DNA testing was a median of 81 days for those receiving CAB-LA (range 41-246) and 11 days for those receiving TDF/FTC (range 3-127). Four (57.1%) of the seven CAB-LA cases with infection had a low initial DNA result [three detected 6 PBMCs); in 2/4 cases, the DNA level was still <10 copies/10⁶ PBMCs ≥40 weeks after the first HIV-positive visit. In contrast, only 3/14 (21.4%) of the TDF/FTC cases had a low or negative initial DNA test result (one not detected; two <10 copies/10⁶ PBMCs). In this study, the time between the first HIV-positive visit and the first DNA test was longer in the CAB-LA cases than the TDF/FTC cases. Despite this difference, low or undetectable DNA levels were more frequently observed in the CAB-LA cases. This suggests that CAB-LA exposure may limit seeding of the HIV reservoir in early infection.

HIV RNA plasma viral load (VL) is the standard surrogate marker to monitor response to antiretroviral treatment (ART). We compared the linearity, repeatability, and concordance of six commercially available HIV RNA VL platforms using clinical samples from patients from Brazilian sites where different HIV-1 subtypes co-circulate. A total of 150 plasma samples from each city were collected in Curitiba, Southern Brazil (subtype C), São Paulo (subtype B), and Santos (BF recombinants), Southeast Brazil. Platforms were VERSANT^® Siemens HIV RNA 1.0 (kPCR); VERSANT^® Siemens HIV-1 RNA 3.0 (bDNA); Abbott Real-Time HIV-1; NucliSens EasyQ^® HIV-1 v2.0 Biomerieux; COBAS^® TaqMan^®, Roche; and artus HIV Virus-1 RT-PCR, QIAGEN. OptiQuant HIV-1 RNA quantification panel was used to compare VL linearity, using samples containing 50, 500,5,000, 50,000, 500,000, and 5,000,000 HIV copies/mL. HIV RNA panels with subtypes A, B, C, D, F, G, H, circulating recombinant form (CRF)1, and CRF2 were utilized. A high degree of linearity and repeatability was demonstrated for all platforms. When compared with a subtype B reference sample, 17 of 54 (31.48%) samples diverged by more than 0.5 log₁₀ copies/mL. Except for the Roche platform, all platforms underestimated subtype C VLs. A total of 743 (82.6%) valid results were obtained with samples from São Paulo, 707 (78.6%) from Santos, and 673 (74.8%) from Curitiba (São Paulo vs. Santos, p = .03; São Paulo vs. Curitiba, p = .00006; Santos vs. Curitiba, p = .06). The number of discordant samples between different methodologies when VL was undetectable in one method and detectable in the other ranged from 1.25% (Abbot vs. Siemens) to 44.8% (Abbott vs. Biomerieux). Finding samples with undetectable VL in one method and a high VL in another might have important individual and public health consequences. Standardization of VL measurements, particularly for non-B subtypes infections, especially subtype C, is necessary to maximize the individual and public health benefits of ART globally.

Central memory (T_CM) cells are a subpopulation of CD4 T cells that sustain overall CD4 T cell counts in HIV infection. The mechanisms underlying their eventual demise, which leads to loss of CD4 T cell counts, are not known. To understand their proneness to death despite their increased movement to proliferation, we examined cell division together with possible cell accumulation in different phases of the cell cycle. Purified circulating T_CM cells from untreated people living with HIV (PLWH) (n = 9) and healthy controls (n = 10) were stimulated in vitro using anti-CD3/CD28 agonistic antibodies plus IL-2 and cultured for 4 days. Cell viability, DNA content, proliferation, and cyclin A and cyclin B expression were measured. We found that PLWH T_CM cells more frequently had a DNA content lower than G0/G1, compared with controls (p = .043). These cells accumulated with each division. The proportion of cells with sub-G0/G1 DNA content that were cycling (expressing cyclin A) was greater in the PLWH group (p = .003). The percentage of T_CM cells expressing cyclin A+ among those in G0/G1 and was also greater in the PLWH group (p = .043), suggesting arrest before G2/M. While T_CM cells from PLWH can proliferate, during this process some of them accumulate defects in DNA content that are incompatible with viability, suggesting that they could be intrinsically prone to cell cycle-dependent death. This provides a possible mechanism underlying the increased T_CM cell turnover in HIV infection.

The recently Food and Drug Administration (FDA)-approved cabotegravir (CAB) has demonstrated efficacy as an antiretroviral agent for HIV treatment and prevention, becoming an important tool to stop the epidemic in the United States of America (USA). However, the effectiveness of CAB can be compromised by the presence of specific integrase natural polymorphisms, including T97A, L74M, M50I, S119P, and E157Q, particularly when coupled with the primary drug-resistance mutations G140S and Q148H. CAB's recent approval as a pre-exposure prophylaxis (PrEP) may increase the number of individuals taking CAB, which, at the same time, could increase the number of epidemiological implications. In this context, where resistance mutations, natural polymorphisms, and the lack of drug-susceptibility studies prevail, it becomes imperative to comprehensively investigate concerns related to the use of CAB. We used molecular and cell-based assays to assess the impact of T218I and T218S in the context of major resistance mutations G140S/Q148H on infectivity, integration, and resistance to CAB. Our findings revealed that T218I and T218S, either individually or in combination with G140S/Q148H, did not significantly affect infectivity, integration, or resistance to CAB. Notably, these polymorphisms also exhibited neutrality concerning other widely used integrase inhibitors, namely raltegravir, elvitegravir, and dolutegravir. Thus, our study suggests that the T218I and T218S natural polymorphisms are unlikely to undermine the effectiveness of CAB as a treatment and PrEP strategy.

Only one study to date has focused on people living with HIV (PLWH) who refused to participate in a HIV cure/remission-related clinical trial (HCCT)-"decliners" hereafter-that included analytical treatment interruption (ATI). Exploring why these persons refuse may provide valuable information to ensure more ethical recruitment and support in HCCTs within the bigger picture of improving HIV cure research. The qualitative component of the AMEP-EHVA-T02/ANRS-95052 study, called AMEP-Decliners, documented the experiences of French PLWH who refused to participate in EHVA-T02/ANRS-VRI07, a phase II randomized, placebo-controlled HCCT with ATI. AMEP-Decliners comprised semi-structured individual interviews with six decliners in two HIV care sites in France between September 2022 and March 2023. The interviews documented their expectations regarding HCCTs, reasons for refusal, and perceived factors that might have led them to participate. Audio files were transcribed, and an inductive thematic analysis was performed. Surprisingly, the main reason for refusal was not ATI but the trial monitoring. Besides the frequency of appointments, respondents emphasized the incompatibility with their active life. One underlying reason for refusal was that participating would have meant "break[ing] the carefree attitude about the disease," reflecting the substantial psychological burden associated with participation. Finally, respondents perceived that the trial's clinical team did not sufficiently recognize their "normal life" and the level of commitment required to participate, leading them to call for greater involvement by the team: "they have to make an effort too." Results from decliners' discourses highlighted that two levels of commitment to participation must be considered when developing HCCTs: psychological burden and logistical constraints. We suggest allowing home examinations and flexible appointment times, prioritizing face-to-face invitations in order to address the psychological burden associated with HCCT participation, and explaining the reasons for monitoring constraints when they cannot be alleviated. Further studies are necessary to confirm our results.

When an initial antiretroviral therapy (ART) regimen is effective and well-tolerated, it can be maintained for years as long as the patient adheres. Prior research has revealed that shorter initial ART duration is associated with regimen type, female sex, injection drug use as the HIV transmission category, and lower baseline CD4 count. We examined potential factors associated with initial regimen discontinuation among a subset of newly diagnosed virally unsuppressed PWH in the DC Cohort, an ongoing prospective observation study that uses electronic health record data from clinic sites to collect relevant information, including demographic and clinical information. Participants were excluded from the analysis if they had less than 6 months of follow-up and were virally suppressed at enrollment. There were 479 individuals included in the study. The median age of participants was 33.9 years [interquartile range (IQR) 26-43.9]. The sample was predominantly male (79.1%) and of Black race (70.8%). Over half of the study participants (56.4%) attended community-based clinic sites. The median time to the discontinuation of initial ART was 2.7 years [95% confidence interval (CI): 2.3, 3.4]. Females had a shorter time to ART discontinuation [adjusted hazard ratio (aHR) 1.55, 95% CI: 1.14, 2.11] as did individuals who started on a protease inhibitor-based regimen versus integrase strand transfer inhibitors (aHR 1.87, 95% CI: 1.34, 2.61) and those receiving HIV care at a community-based site (aHR 1.46, 95% CI: 1.11,1.93). Although limited by lack of reason for discontinuation, we demonstrated that ART-naïve women, community clinic attendees, and patients starting on PIs had a shorter duration of initial ART. More anticipatory guidance may be needed to help patients stay on their initial therapy and manage the side effects or to be flexible in trying different regimens.

The border areas of Yunnan Province in China are severely affected by human immunodeficiency virus (HIV). To investigate the risk of HIV transmission and assess the prevalence of pretreatment drug resistance (PDR) in the border area, blood samples were collected from individuals with newly reported HIV in 2021 in three border counties (Cangyuan, Gengma, and Zhenkang) in Yunnan Province. Among the 174 samples successfully genotyped, eight circulating recombinant forms (CRFs), two subtypes, and several unique recombinant forms (URFs) were identified. CRF08_BC (56.9%, 99/174), URFs (14.4%, 25/174), CRF01_AE (10.9%, 19/174), and CRF07_BC (8.0%, 14/174) were the main genotypes. CRF08_BC and URFs were detected more frequently in Chinese and Burmese individuals, respectively. CRF07_BC was found more frequently in men who have sex with men. The proportion of individuals detected in HIV-1 networks was only associated with case-reporting counties. When stratified by county, individuals aged ≤40 years in Cangyuan and ≥41 years in Gengma were more likely to be found in these networks. Furthermore, 93.8% (15/16) of the links in Cangyuan and 79.4% (50/63) of those in Gengma were located within their own counties. The prevalence of PDR to any antiretroviral drug, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were 10% (17/170), 0.6% (1/170), and 9.4% (16/170), respectively. The most frequent resistance-associated mutations (RAMs) were V179D/VD/E/T (22.9%, 39/170) and E138A/G/K/R (13.5%, 23/170). In the molecular networks, six clusters shared common RAMs. HIV-1 genetics has become more diverse in border areas. HIV-1 molecular network analysis revealed the different characteristics of the HIV-1 epidemic in the border counties. The prevalence of PDR showed an upward trend, and the PDR to NNRTIs was close to the public response threshold. These findings provide information for the development of AIDS prevention and treatment strategies.

Transgender women are disproportionately burdened by HIV. Though there is a substantial body of research exploring barriers and facilitators of HIV prevention among transgender women, many barriers remain unaddressed. This study identifies strategies to make HIV prevention trials more congruent with transgender women's preferences and needs to boost trial participation and ultimately enhance initiation and uptake of pre-exposure prophylaxis (PrEP). We conducted in-depth interviews with 15 sexually active, HIV-negative transgender women in New York City to understand: (1) preferences concerning long-acting injectable cabotegravir for PrEP and (2) ideas on how to make HIV prevention trial environments more comfortable. We identified five themes related to increasing transgender women's appeal to trials: (1) creating a more inclusive/welcoming environment, (2) providing compensation that is responsive to transgender women and community needs, (3) centering transgender women in recruitment and informational materials, (4) training study staff on gender-affirming practices, and (5) hiring transgender people as study staff. Participants wanted to see more gender diversity, representation, correct pronouns, gender-affirming practices, and compensation or reimbursements. Together, these practices may improve recruitment and retention of transgender women in HIV prevention trials.

Continuous recombination and variation during replication could lead to rapid evolution and genetic diversity of HIV-1. Some studies had identified that it was easy to develop new recombinant strains of HIV-1 among the populations of men who have sex with men (MSM). Surveillance of genetic variants of HIV-1 in key populations was crucial for comprehending the development of regional HIV-1 epidemics. The finding was reported the identification of two new unique recombinant forms (URF 20110561 and 21110743) from individuals infected with HIV-1 in Tongzhou, Beijing in 2020-2022. Sequences of near full-length genome (NFLG) were amplified, then identification of amplification products used phylogenetic analyses. The result showed that CRF01_AE was the main backbone of 20110561 and 21110743. In the gag region of the virus, 20110561 was inserted two fragments from CRF07_BC, while in the pol and tat regions of the virus, 21110743 was inserted four fragments from CRF07_BC. The CRF01_AE parental origin in the genomes of the two URFs was derived from the CRF01_AE Cluster 4. In the phylogenetic tree, the CRF07_BC parental origin of 20110561 clustered with 07BC_N and the CRF07_BC parental origin of 21110743 clustered with 07BC_O. In summary, the prevalence of novel second-generation URFs of HIV-1 was monitored in Tongzhou, Beijing. The emergence of the novel CRF01_AE/CRF07_BC recombination demonstrated that there was a great significance of continuous monitoring of new URFs in MSM populations to prevent and control the spreading of new HIV-1 URFs.