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Australia’s response to the human immunodeficiency virus type 1 (HIV-1) pandemic led to effective control of HIV transmission and one of the world’s lowest HIV incidence rates—0.14%. Although there has been a recent decline in new HIV diagnoses in New South Wales (NSW), the most populous state in Australia, there has been a concomitant increase with non-B subtype infections, particularly for the HIV-1 circulating recombinant form CRF01_(A)E. This aforementioned CRF01_(A)E sampled in NSW, were combined with those sampled globally to identify NSW-specific viral clades. The population growth of these clades was assessed in two-year period intervals from 2009 to 2017. Overall, 109 NSW-specific clades were identified, most comprising pairs of sequences; however, five large clades comprising ≥10 sequences were also found. Forty-four clades grew over time with one or two sequences added to each in different two-year periods. Importantly, while 10 of these clades have seemingly discontinued, the remaining 34 were still active in 2016/2017. Seven such clades each comprised ≥10 sequences, and are representative of individual sub-epidemics in NSW. Thus, although the majority of new CRF01_(A)E infections were associated with small clades that rarely establish ongoing chains of local transmission, individual sub-epidemics are present and should be closely monitored.

Abstract Human immunodeficiency virus type 1 (HIV-1) remains a serious health threat in Indonesia. In particular, the CRF01_(A)E viruses were the predominant HIV-1 strains in various cities in Indonesia. However, information on the dynamic transmission characteristics and spatial–temporal transmission of HIV-1 CRF01_(A)E in Indonesia is limited. Therefore, the present study examined the spatial–temporal transmission networks and evolutionary characteristics of HIV-1 CRF01_(A)E in Indonesia. To clarify the epidemiological connection between CRF01_(A)E outbreaks in Indonesia and the rest of the world, we performed phylogenetic studies on nearly full genomes of CRF01_(A)E viruses isolated in Indonesia. Our results showed that five epidemic clades, namely, IDN clades 1–5, of CRF01_(A)E were found in Indonesia. To determine the potential source and mode of transmission of CRF01_(A)E, we performed Bayesian analysis and built maximum clade credibility trees for each clade. Our study revealed that CRF01_(A)E viruses were commonly introduced into Indonesia from Southeast Asia, particularly Thailand. The CRF01_(A)E viruses might have spread through major pandemics in Asian countries, such as China, Vietnam, and Laos, rather than being introduced directly from Africa in the early 1980s. This study has major implications for public health practice and policy development in Indonesia. The contributions of this study include understanding the dynamics of HIV-1 transmission that is important for the implementation of HIV disease control and prevention strategies in Indonesia.

Background HIV-1 CRF01_(A)E exhibits multiple distinct sub-subtypes (01_(C)1-C8) with different transmission dynamics across China. Understanding their geographical distribution, transmission patterns, and key affected populations is critical for optimizing targeted interventions.Methods We conducted a comprehensive molecular epidemiological study analyzing 4,011 partial pol sequences and demographic data from newly diagnosed CRF01_(A)E cases (2016–2019) in Shenyang (Northeast China) and Shenzhen (South China) by constructing the CRF01_(A)E molecular network in China (n = 6140). Sub-subtyping was performed using an online HIV subtyping tool and phylogenetic analysis. A molecular network was constructed based on genetic distance, and viral dispersal in large clusters (size≥10) in the network was assessed using Bayesian inference.Results 01_(C)5 (46.7%), 01_(C)4 (37.2%), 01_(C)1 (8.1%), 01_(C)2 (2.3%), 01_(C)3 (0.3%), and 01_(C)8 (<0.1%) were detected, with 01_(C)5 (73.7%) dominating in Shenyang, and 01_(C)4 (53.0%) in Shenzhen. Molecular network analysis revealed 24 large clusters, including 12 01_(C)5 clusters (64.7%) and 10 01_(C)4 clusters (28.5%). Notably, 01_(C)5 accounted for 75.9% of the mixed large clusters containing sequences from both cities. Bayesian phylodynamic analysis indicated one-way transmission of 01_(C)5 from Shenyang to Shenzhen was driven by middle-aged MSM (30–49 years old).Conclusion Our findings provided a potential molecular epidemiological evidence for CRF01_(A)E transmission from Northeast China to South China, and highlighted the urgent need for targeted interventions focusing on middle-aged MSM to prevent cross-regional 01_(C)5 transmission. This study provided an example for applying traceability analysis based on the HIV molecular transmission network in guiding targeted public health interventions.

The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics. The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. The gp120 inner domain topological layers facilitate the transition of Env to the CD4-bound conformation. CD4 engages gp120 by introducing its phenylalanine 43 (Phe43) in a cavity (“the Phe43 cavity”) located at the interface between the inner and outer gp120 domains. Small CD4-mimetic compounds (CD4mc) can bind within the Phe43 cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe43 cavity and shaping the CD4 binding site. Our studies reveal a complex interplay between the gp120 inner domain and the Phe43 cavity and generate useful information for the development of more-potent CD4mc. IMPORTANCE The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics.

Identifying immunogens which can elicit effective T cell responses against human immunodeficiency virus type 1 (HIV-1) is important for developing a T-cell based vaccine. It has been reported that human leukocyte antigen (HLA)-B*13-restricted T-cell responses contributed to HIV control in subtype B' and C infected individuals. However, the kinetics of B*13-restricted T-cell responses, viral evolution within epitopes, and the impact on disease progression in CRF01_(A)E subtype HIV-1-infected men who have sex with men (MSM) are not known. Interferon-[gamma] ELISPOT assays and deep sequencing of viral RNAs were done in 14 early HLA-B*13-positive CRF01_(A)E subtype HIV-1-infected MSM. We found that responses to RQEILDLWV (Nef.sub.106-114, RV9), GQMREPRGSDI (Gag.sub.226-236, GI11), GQDQWTYQI (Pol.sub.487-498, GI9), and VQNAQGQMV (Gag.sub.135-143, VV9) were dominant. A higher relative magnitude of Gag-specific T-cell responses, contributed to viral control, whereas Nef-specific T-cell responses were associated with rapid disease progression. GI11 (Gag) was conserved and strong GI11 (Gag)-specific T-cell responses showed cross-reactivity with a dominant variant, M228I, found in 3/12 patients; GI11 (Gag)-specific T-cell responses were positively associated with CD4 T-cell counts (R = 0.716, P = 0.046). Interestingly, the GI9 (Pol) epitope was also conserved, but GI9 (Pol)-specific T-cell responses did not influence disease progression (P > 0.05), while a D490G variant identified in one patient did not affect CD4 T-cell counts. All the other epitopes studied [VV9 (Gag), RQYDQILIEI (Pol.sub.113-122, RI10), HQSLSPRTL (Gag.sub.144-152, HL9), and RQANFLGRL (Gag.sub.429-437, RL9)] developed escape mutations within 1 year of infection, which may have contributed to overall disease progression. Intriguingly, we found early RV9 (Nef)-specific T-cell responses were associated with rapid disease progression, likely due to escape mutations. Our study strongly suggested the inclusion of GI11 (Gag) and exclusion of RV9 (Nef) for T-cell-based vaccine design for B*13-positive CRF01_(A)E subtype HIV-1-infected MSM and high-risk individuals.

Background In China, an HIV-infected man (complainant; P2) alleged that another man (defendant; P1) had unlawfully infected him with HIV through unprotected homosexual contact in 2018. Methods We employed epidemiological, serological and phylogenetic analyses to investigate the transmission linkage between two men who have sex with men (MSM). Partial segments of three HIV-1 gene regions ( gag , pol , and env ) were amplified and sequenced by cloning. Maximum-likelihood (ML) and Bayesian methods were used to determine the direction and estimate the timing of transmission. Local control sequences and database control sequences were also used in the phylogenetic analysis. Results It indicated that P2 underwent HIV seroconversion after P1 was diagnosed as HIV positive. The time to the most recent common ancestor (tMRCA) estimates consistently showed that P1 most likely became HIV-1 infected at an earlier date than P2. P1 and P2 were infected with the same HIV-1 CRF01_AE subtype according to segments of all three gene regions ( gag , pol , and env ). All three genetic regions of P1 have been subject to more potential selective forces than those of P2, indicating a longer evolutionary history. Bayesian and ML trees showed similar paraphyletic-monophyletic topologies of gag and env , with the virus from P1 located at the root, which supported a P1-to-P2 transmission direction. Conclusions Phylogenetic investigations can elucidate HIV transmission linkage and might empower its use in the opposition of the intentional transmission of HIV-1 as a forensic tool.

Background: In China, two distinct lineages shaped the epidemic of HIV-1 CRF01_(A)E among men who have sex with men (MSM), of which the uneven distributions were observed geographically. One lineage spread across China, while another dominated in Northeast China. Understanding the drivers of viral diffusion would provide guidelines for identifying the source and hotspots of HIV transmission among MSM to target interventions in China. Methods: We collected the pol sequences between 2002–2017 to reconstruct the spatiotemporal history of CRF01_(A)E lineages in Shenyang, one economic center of Northeast China, using the Bayesian phylogeographic and phylodynamic approaches. Importantly, for the datasets with the high sample density, we did the down-sampling to avoid the sampling bias. Results: Two lineages accounted for 97%, including 426 and 1516 sequences, and homosexuals and bisexuals were above 80%. One lineage appeared earlier 7 years than another (1993 vs. 2002) among homosexuals and bisexuals, whereas among heterosexuals, both lineages were observed firstly in 2002. 96% viral migrations within one lineage were from homosexuals toward bisexuals (49%) and male-heterosexuals (46%). Within another, except for homosexuals (72%), bisexuals (23%) served as the top second source, and female-heterosexuals (11%) were the third recipients following bisexuals (44%) and male-heterosexuals (39%). Although the basic reproduction number (R0) of two lineages were similar and both of the effective production number (Re) fell below 1 at the most recent sampling time, the starts of the Re declining varied. Conclusions: Our findings revealed that throughout the viral national spread chain, Shenyang is the source for the initial expanding of one lineage, where is only a sink of another, proving that the viral founder effect and regional human mobility contributed to the uneven distribution of two lineages, and emphasizing the important roles of the area where the virus originated and economy-driven migrants in HIV transmission.

Infants acquire maternal antibodies by Fc receptor transcytosis across the placenta during pregnancy. Fc receptors are expressed on immune cells and are important for activation of effector cell functions. In this study, we evaluated Fc receptor engagement and ADCC activity of plasma binding antibodies from human immunodeficiency virus-1 (HIV) -infected mothers and to identify factors that may contribute to protection from HIV vertical transmission. HIV-specific binding and Fc receptor engagement of plasma antibodies varied between mothers by transmission status and infants by infection status. Non-transmitting (NT) mothers and HIV-uninfected infants had antibodies with higher neonatal Fc receptor (FcRn) and FcγR engagement, as compared to transmitting (T) mothers and HIV+ infants, respectively. A significant inverse correlation between plasma antibody FcRn and FcγR engagement was observed for T mothers, but not NT mothers. Conversely, a significant direct correlation was observed between plasma antibody FcRn and FcγR engagement for HIV- infants, but not for HIV+ infants. Consequently, we observed significantly higher plasma antibody ADCC potency and breadth in HIV- infants, as compared to HIV+ infants. However, no differences in overall ADCC potency and breadth were observed between mothers. FcRn-engagement of HIV-specific antibodies in both mothers and infants predicted a lack of vertical transmission of HIV. This study indicates that HIV-uninfected infants acquire HIV-specific antibodies with greater Fc receptor engagement and thus, greater ADCC capacity.

One of the major goals in HIV-1 vaccine development is to achieve properly folded and stabilized envelope glycoprotein (Env) trimers that mimic the native Env on the mature virion. Here, we design and characterize uncleaved prefusion-optimized (UFO) trimers for 12 Envs currently circulating in China. Biochemical and biophysical characterization of these UFO trimers identified two subtype B/Bʹ Envs, CNE6 and MG13, which exhibited the highest trimer content and stability at a level comparable to the subtype A reference, BG505. Replacing the gp41 ectodomain (gp41 ECTO ) of CRF01_AE trimers with that of CNE6, MG13, and BG505 resulted in chimeric constructs with significantly improved trimer content and stability. Negative-stain electron microscopy (EM) confirmed the structural integrity of these chimeric UFO trimers with CNE6 gp41 ECTO . Antibody binding assays showed that the chimeric trimers shared similar antigenic profiles to those with their original gp41 ECTO domains. Our results thus revealed the intrinsic differences among HIV-1 Envs of diverse origins and the critical role of gp41 ECTO in stabilizing the trimeric spike. By taking advantage of naturally stable Envs, gp41 ECTO swapping may represent a universal approach for the generation of stable trimers with the desired structural and antigenic properties for downstream in vivo evaluation and vaccine development.

The impacts of genetic polymorphisms on drug resistance mutations (DRMs) among various HIV-1 subtypes have long been debated. In this study, we aimed to analyze the natural polymorphisms and acquired DRM profile in HIV-1 CRF01_(A)E-infected patients in a large first-line antiretroviral therapy (ART) cohort in northeastern China. The natural polymorphisms of CRF01_(A)E were analyzed in 2034 patients from a long-term ART cohort in northeastern China. The polymorphisms in 105 treatment failure (TF) patients were compared with those in 1148 treatment success (TS) patients. The acquired DRM profile of 42 patients who experienced TF with tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) treatment was analyzed by comparing the mutations at TF time point to those at baseline. The Stanford HIVdb algorithm was used to interpret the DRMs. Binomial distribution, McNemar test, Wilcoxon test and CorMut package were used to analyze the mutation rates and co-variation. Deep sequencing was used to analyze the evolutionary dynamics of co-variation. Before ART, there were significantly more natural polymorphisms of 31 sites on reverse transcriptase (RT) in CRF01_(A)E than subtype B HIV-1 (|Z value| [greater than or equai to] 3), including five known drug resistance-associated sites (238, 118, 179, 103, and 40). However, only the polymorphism at site 75 was associated with TF (|Z value| [greater than or equai to] 3). The mutation rate at 14 sites increased significantly at TF time point compared to baseline, with the most common DRMs comprising G190S/C, K65R, K101E/N/Q, M184 V/I, and V179D/I/A/T/E, ranging from 66.7 to 45.2%. Moreover, two unknown mutations (V75 L and L228R) increased by 19.0 and 11.9% respectively, and they were under positive selection (Ka/Ks > 1, log odds ratio [LOD] > 2) and were associated with several other DRMs (cKa/Ks > 1, LOD > 2). Deep sequencing of longitudinal plasma samples showed that L228R occurred simultaneously or followed the appearance of Y181C. The high levels of natural polymorphisms in CRF01_(A)E had little impact on treatment outcomes. The findings regarding potential new CRF01_(A)E-specific minor DRMs indicate the need for more studies on the drug resistance phenotype of CRF01_(A)E.