Explore the vast range of titles available.

Introduction Cases of spontaneous control of HIV‐1 can help define strategies to induce remission. Since the identification of viral control in the absence of treatment typically occurs after a prolonged period post‐HIV‐1 diagnosis, our knowledge of the early events after HIV‐1 acquisition that led to viral control is limited. Methods The RV217 prospective cohort enrolled 2276 participants in East Africa (Kenya, Uganda, Tanzania) and Thailand between 2009 and 2015. We analysed HIV‐1 sequences and clinical data from 102 individuals who were diagnosed with acute HIV‐1 infection and had a negative HIV‐1 RNA test in the week before. We focused on 69 participants with longitudinal follow‐up and identified viraemic controllers who maintained viral loads <2000 copies/ml for over a year without treatment. We evaluated viral genetic and clinical features that are associated with viral control. Results Eleven women from East Africa showed control of viral replication for an average duration of 891 (range: 405–1425) days within an average of 130 days from diagnosis. The majority were living with subtype A1 (n = 6), or A1 recombinant strains (n = 4), with one living with subtype D; 10 were from Kenya, one from Uganda. Controllers had significantly slower CD4+ T cell decline (p = 0.028) and higher Natural Killer (NK) cell counts (p = 0.047) than non‐controllers, but none carried human leukocyte antigen (HLA) alleles previously reported to be associated with viral control. Peak viraemia was recorded at an average of 541 million copies/ml with no difference between controllers and non‐controllers (p = 0.97). Viral loads became lower in controllers (3459 copies/ml) than in non‐controllers (23,157 copies/ml) as early as nadir viraemia (p = 0.009), with a more significant difference observed at set point (1069 vs. 24,084 copies/ml, respectively; p<0.0001). Conclusions Our findings confirm the role of HIV‐1 subtype A1 in mediating viral control. The fact that controllers showed high viral loads in acute infection indicates that these viruses were not intrinsically impaired for replication, underlining the intersection between host immunity and favourable genotypes in the subsequent control of HIV‐1. These data suggest that conducting HIV‐1 remission studies in East Africa could provide favourable conditions to achieve durable post‐treatment control of viraemia.

Introduction A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug‐resistant virus that could spread and reduce the effectiveness of non‐nucleoside reverse transcriptase (NNRTI)‐based first‐line antiretroviral therapy. We evaluated HIV‐1 seroconversions in MTN‐020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV. Methods MTN‐020/ASPIRE was a placebo‐controlled, Phase III safety and effectiveness study of DPV ring for HIV‐1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV‐1 drug resistance using both population Sanger sequencing and next‐generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma‐derived recombinant HIV‐1 containing bulk‐cloned full‐length reverse transcriptase sequences from MTN‐020/ASPIRE seroconversions was determined in TZM‐bl cells. Statistical significance was calculated using the Fisher's exact test. Results Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low‐frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others. Conclusions HIV‐1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN‐020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

The predictive factors of HIV-1 drug resistance and its distribution are poorly documented in female sex workers (FSWs) in the Democratic Republic of the Congo (DRC). However, the identification of predictive factors can lead to the development of improved and effective antiretroviral therapy (ART). The objective of the current study was to determine the predictive factors of HIV-1 drug resistance and its distribution based on FSWs in the studied regions in the Democratic Republic of the Congo (DRC). HIV-positive FSWs who were diagnosed as part of the DRC Integrated Biological and Behavioral Surveillance Survey (IBBS) were included in this study. A total of 325 FSWs participated. The HIV-1 viral load (VL) was measured according to the Abbott m2000sp and m2000rt protocols. The homogeneity chi-square test was conducted to determine the homogeneity of HIV-1 drug resistance distribution. Using a significance level of 0.05, multivariate analyses were performed to identify factors associated with HIV-1 drug resistance to ART. HIV drug resistance mutation (HIVDRM) distribution was homogeneous in the three study regions (p = 0.554) but differed based on the HIV-1 VLs of the FSWs. FSWs with high HIV-1 VLs harbored more HIVDRMs (p = 0.028) of predominantly pure HIV-1 strains compared with those that had low HIV-1 VLs. Sexually transmitted infection (STI) history (aOR [95%CI] = 8.51 [1.62, 44.74]), high HIV-1 VLs (aOR [95%CI] = 5.39 [1.09, 26.74]), and HIV-1–syphilis coinfection (aOR [95%CI] = 9.71 [1.84, 51.27]) were associated with HIV drug resistance among FSWs in the DRC. A history of STIs (e.g., abnormal fluid) in the 12 months prior to the survey, a high HIV-1 VL, and HIV-1–syphilis coinfection were associated with HIV-1 drug resistance among FSWs in the DRC. Efforts should be made to systematically test for other infections which increase the HIV-1 VL, in the case of HIV-1 coinfection, in order to maintain ART effectiveness across the DRC.

Introduction There is limited data in children on whether persistence of HIV‐1 infected cells is affected by age at initiating antiretroviral therapy (ART), its duration or any subsequent ART interruption. We therefore investigated the effects of both age of ART initiation and duration of ART interruption on HIV‐1 DNA decay in children. Methods We investigated HIV‐1 DNA decay in three groups of children on ART: Group‐1 (n = 7) started uninterrupted ART within eight days of life; Group‐2 (n = 8) started uninterrupted ART at a median of five months of age; and Group‐3 (n = 23) started ART at a median age of 1.8 months for either 40 or 96 weeks, then interrupted ART (median of seven months), and restarted ART based on CD4 count and clinical criteria. Total HIV‐1 DNA was assayed using a sensitive HIV‐1 subtype C‐adapted quantitative PCR for integrase. The duration of ART was square root transformed to fit the observed slowing of HIV‐1 DNA decay rate. For each group, point estimates for decay rates were determined after six months of continuous suppressive ART in groups 1 and 2 or six months after restarting ART in Group‐3. Groups‐2 and 3 were combined using a mixed effect regression model to investigate covariates of HIV‐1 DNA decay rate. Results and Discussion At six months of continuous suppressive ART, the HIV‐1 DNA t½ (95% CI) was shorter in Group‐1 (n = 7): 2.7 months (2.1 to 3.8), than 9.2 months (7.4 to 12.1) in Group‐2 (n = 8); and 9.6 months (7.6 to 12.6) in Group‐3 (n = 23) (p < 0.01). In multivariable analyses, HIV‐1 DNA before treatment (p < 0.001) and the change in HIV‐1 DNA during interruption (p < 0.01) were independent predictors of slower HIV‐1 DNA decay. Conclusions These data suggest that ART initiation within the first week of life can reduce the persistence of long‐lived infected cells. Delaying ART is associated with slower decay of infected cells.

Introduction A primary focus of HIV‐1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity‐matured bnAbs. HIV‐1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV‐1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs. Methods We provide perspectives based on published research articles and reviews. Discussion The recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV‐1 Env bnAb specificity demonstrated that relatively high levels of long‐lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV‐1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV‐1 bnAb precursor B cells following the recent success of vaccine‐induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming‐immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV‐1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation. Conclusions A fully protective HIV‐1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV‐1 strains during transmission.

Since the introduction of combined antiretroviral therapy, acquired immune deficiency syndrome (AIDS)‐related lymphomas account for a growing proportion of deaths among people living with human immunodeficiency virus (PLWHIV). In addition to the immune deficiency caused by AIDS and other cofactors, it has been shown that circulating HIV‐1 proteins play a critical role in lymphoma development. The HIV‐1 matrix protein p17 (refp17) is released from infected cells and accumulates in lymph nodes of PLWHIV, even during effective pharmacological control of viral replication. Circulating refp17 deregulates the biological activity of different immune cells. Moreover, p17 variants (vp17s) characterized by peculiar amino acid insertions occurring in the C‐terminal region of the protein, differently from the refp17, also induce B‐cell growth and clonogenicity. Notably, vp17s were found at a significantly higher prevalence in PLWHIV with than without lymphoma. HIV‐1 mutants expressing clonogenic vp17s are actively spreading, and their prevalence is globally increasing worldwide. RNA viruses exist as a population of quasi‐species, transmitted from one host to another, which ultimately leads to viral evolution by generating new master sequences. Here, we developed a next‐generation sequence approach to evaluate the frequency of vp17 quasi‐species in PLWHIV upon time and demonstrated that the incidence of vp17s also increases at quasi‐species levels. Additionally, we established a regression model capable of predicting the insertions with higher probability to be fixed, further highlighting the evolutionary relevance of the C‐terminal region in the adaptation of p17 to the human host. HIV‐1 mutants expressing clonogenic HIV‐1 matrix protein p17 variants (vp17s) are spreading, increasing their prevalence worldwide. In RNA viruses, quasi‐species are transmitted among hosts, leading to the generation of new master sequences. We developed a next‐generation sequence approach to evaluate the frequency of vp17 quasi‐species in people living with human immunodeficiency virus, demonstrating their increased incidence.

The major structural elements of retroviruses are contained in a single polyprotein, Gag, which in human immunodeficiency virus type 1 (HIV‐1) comprises the MA, CA, spacer peptide 1 (SP1), NC, SP2, and p6 polypeptides. In the immature HIV‐1 virion, the domains of Gag are arranged radially with the N‐terminal MA domain at the membrane and C‐terminal NC‐SP2‐p6 region nearest to the center. Here, we report the three‐dimensional structures of individual immature HIV‐1 virions, as obtained by electron cryotomography. The concentric shells of the Gag polyprotein are clearly visible, and radial projections of the different Gag layers reveal patches of hexagonal order within the CA and SP1 shells. Averaging well‐ordered unit cells leads to a model in which each CA hexamer is stabilized by a bundle of six SP1 helices. This model suggests why the SP1 spacer is essential for assembly of the Gag lattice and how cleavage between SP1 and CA acts as a structural switch controlling maturation.

Primate genomes encode a variety of innate immune strategies to defend themselves against retroviruses. One of these, TRIM5α, can restrict diverse retroviruses in a species-specific manner. Thus, whereas rhesus TRIM5α can strongly restrict HIV-1, human TRIM5α only has weak HIV-1 restriction. The biology of TRIM5α restriction suggests that it is locked in an antagonistic conflict with the proteins encoding the viral capsid. Such antagonistic interactions frequently result in rapid amino acid replacements at the protein-protein interface, as each genetic entity vies for evolutionary dominance. By analyzing its evolutionary history, we find strong evidence for ancient positive selection in the primate TRIM5α gene. This selection is strikingly variable with some of the strongest selection occurring in the human lineage. This history suggests that TRIM5α evolution has been driven by antagonistic interactions with a wide variety of viruses and endogenous retroviruses that predate the origin of primate lentiviruses. A 13-aa \"patch\" in the SPRY protein domain bears a dense concentration of positively selected residues, potentially implicating it as an antiviral interface. By using functional studies of chimeric TRIM5α genes, we show that this patch is generally essential for retroviral restriction and is responsible for most of the species-specific antiretroviral restriction activity. Our study highlights the power of evolutionary analyses, in which positive selection identifies not only the age of genetic conflict but also the interaction interface where this conflict plays out.

Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results. Mean change in HIV-1 RNA at day 8 was -1.43 log₁₀ c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions. DTG 50 mg BID-based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).

The latent viral reservoir is the source of viral rebound after interruption of antiretroviral therapy (ART) and is the major obstacle in eradicating the latent human immunodeficiency virus‐1 (HIV‐1). In this study, arsenic class of mineral, arsenic trioxide, clinically approved for treating acute promyelocytic leukemia, is demonstrated to reactivate latent provirus in CD4+ T cells from HIV‐1 patients and Simian immunodeficiency virus (SIV)‐infected macaques, without significant systemic T cell activation and inflammatory responses. In a proof‐of‐concept study using chronically SIVmac239‐infected macaques, arsenic trioxide combined with ART delays viral rebound after ART termination, reduces the integrated SIV DNA copies in CD4+ T cells, and restores CD4+ T cells counts in vivo. Most importantly, half of arsenic trioxide‐treated macaques show no detectable viral rebound in the plasma for at least 80 days after ART discontinuation. Mechanistically, the study reveals that CD4 receptors and CCR5 co‐receptors of CD4+ T cells are significantly downregulated by arsenic trioxide treatment, which reduces susceptibility to infection after provirus reactivation. Furthermore, an increase in SIV‐specific immune responses after arsenic trioxide treatment may contribute to suppression of viral rebound. This work suggests that arsenic trioxide in combination with ART is a novel regimen in down‐sizing or even eradicating latent HIV‐1 reservoir. In combination with antiretroviral therapy (ART), treatment with arsenic trioxide delays viral rebound, and half of treated macaques show no detectable rebound for 80 days, after ART discontinuation in chronically simian immunodeficiency virus‐infected macaques, without devastating T cell activation and proinflammatory responses. The mechanism for this potentially functional cure of human immunodeficiency virus may involve multiple modes acting synergistically.