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.

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.

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.