Novel HLA class I associations with HIV-1 control in a unique genetically admixed population.

Associations between HLA class I alleles and HIV progression in populations exhibiting Amerindian and Caucasian genetic admixture remain understudied. Using univariable and multivariable analyses we evaluated HLA associations with five HIV clinical parameters in 3,213 HIV clade B-infected, ART-naïve individuals from Mexico and Central America (MEX/CAM cohort). A Canadian cohort (HOMER, n = 1622) was used for comparison. As expected, HLA allele frequencies in MEX/CAM and HOMER differed markedly. In MEX/CAM, 13 HLA-A, 24 HLA-B, and 14 HLA-C alleles were significantly associated with at least one clinical parameter. These included previously described protective (e.g. B*27:05, B*57:01/02/03 and B*58:01) and risk (e.g. B*35:02) alleles, as well as novel ones (e.g. A*03:01, B*15:39 and B*39:02 identified as protective, and A*68:03/05, B*15:30, B*35:12/14, B*39:01/06, B*39:05~C*07:02, and B*40:01~C*03:04 identified as risk). Interestingly, both protective (e.g. B*39:02) and risk (e.g. B*39:01/05/06) subtypes were identified within the common and genetically diverse HLA-B*39 allele group, characteristic to Amerindian populations. While HLA-HIV associations identified in MEX and CAM separately were similar overall (Spearman's rho = 0.33, p = 0.03), region-specific associations were also noted. The identification of both canonical and novel HLA/HIV associations provides a first step towards improved understanding of HIV immune control among unique and understudied Mestizo populations.

Identification of major routes of HIV transmission throughout Mesoamerica.

BACKGROUND: Migration and travel are major drivers of the spread of infectious diseases. Geographic proximity and a common language facilitate travel and migration in Mesoamerica, which in turn could affect the spread of HIV in the region. METHODS: 6092 HIV-1 subtype B partial pol sequences sampled from unique antiretroviral treatment-naïve individuals from Mexico (40.7%), Guatemala (24.4%), Honduras (19%), Panama (8.2%), Nicaragua (5.5%), Belize (1.4%), and El Salvador (0.7%) between 2011 and 2016 were included. Phylogenetic and genetic network analyses were performed to infer putative relationships between HIV sequences. The demographic and geographic associations with clustering were analyzed and viral migration patterns were inferred using the Slatkin-Maddison approach on 100 iterations of random subsets of equal number of sequences per location. RESULTS: A total of 1685/6088 (27.7%) of sequences linked with at least one other sequence, forming 603 putative transmission clusters (range: 2-89 individuals). Clustering individuals were significantly more likely to be younger (median age 29 vs 33years, p<0.01) and men-who-have-sex-with-men (40.4% vs 30.3%, p<0.01). Of the 603 clusters, 30 (5%) included sequences from multiple countries with commonly observed linkages between Mexican and Honduran sequences. Eight of the 603 clusters included >10 individuals, including two comprised exclusively of Guatemalans (52 and 89 individuals). Phylogenetic and migration analyses suggested that the Central and Southern regions of Mexico along with Belize were major sources of HIV throughout the region (p<0.01) with genetic flow southward from Mexico to the other nations of Mesoamerica. We also found evidence of significant viral migration within Mexico. CONCLUSION: International clusters were infrequent, suggesting moderate migration between HIV epidemics of the different Mesoamerican countries. Nevertheless, we observed important sources of transnational HIV spread in the region, including Southern and Central Mexico and Belize.

Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.

OBJECTIVE: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. METHODS: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. RESULTS: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. CONCLUSIONS: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

HIV and hepatitis B and C incidence rates in US correctional populations and high risk groups: a systematic review and meta-analysis.

BACKGROUND: High Human Immunodeficiency Virus (HIV) prevalence and high risk behaviors have been well documented within United States (US) correctional systems. However, uncertainty remains regarding the extent to which placing people in prison or jail increases their risk of HIV infection, and regarding which inmate populations experience an increased incidence of HIV. Describing these dynamics more clearly is essential to understanding how inmates and former detainees may be a source for further spread of HIV to the general US population. METHODS: The authors conducted a systematic review and meta-analysis of studies describing HIV incidence in US correctional facility residents and, for comparison, in high risk groups for HIV infection, such as non-incarcerated intravenous drug users (IVDU) and men who have sex with men (MSM) in the US. HIV incidence rates were further compared with Hepatitis B and Hepatitis C Virus rates in these same populations. RESULTS: Thirty-six predominantly prospective cohort studies were included. Across all infection outcomes, continuously incarcerated inmates and treatment recruited IVDU showed the lowest incidence, while MSM and street recruited IVDU showed the highest. HIV incidence was highest among inmates released and re-incarcerated. Possible sources of heterogeneity identified among HIV studies were risk population and race. CONCLUSIONS: Although important literature gaps were found, current evidence suggests that policies and interventions for HIV prevention in correctional populations should prioritize curtailing risk of infection during the post-release period. Future research should evaluate HIV incidence rates in inmate populations, accounting for proportion of high risk sub-groups.