Worldwide Genetic Features of HIV-1 Env α4β7 Binding Motif: The Local Dissemination Impact of the LDI Tripeptide

Abstract

Background: HIV-1 gp120 binds to integrin α4β7, a homing receptor of lymphocytes to gut-associated lymphoid tissues. This interaction is mediated by the LDI/V tripeptide encoded in the V2-loop. This tripeptide mimics similar motifs in mucosal addressin cellular adhesion molecule (MAdCAM) and vascular CAM (VCAM), the natural ligands of α4β7. In this study, we explored the association of V2-loop LDI/V mimotopes with transmission routes and patterns of disease progression in HIV-infected adult and pediatric patients. HIV-1 env sequences available in the Los Alamos HIV Sequence database were included in the analyses.

Methods: HIV-1 V2-loop sequences generated from infected adults and infants from South and Southeast Brazil, and also retrieved from the Los Alamos database, were assessed for α4β7 binding tripeptide composition. Chi-Square/Fisher Exact test and Mann Whitney U test were used for tripeptide comparisons. Shannon entropy was assessed for conservancy of the α4β7 tripeptide mimotope.

Results: We observed no association between the tripeptide composition or conservation and virus transmission route or disease progression. However, LDI was linked to successful epidemic dissemination of HIV-1 subtype C in South America, and further to other expanding non-B subtypes in Europe and Asia. In Africa, subtypes showing increased LDV prevalence evidenced an ongoing process of selection toward LDI expansion, an observation also extended to subtype B in the Americas and Western Europe.

Conclusions: The V2-loop LDI mimotope was conserved in HIV-1C from South America and other expanding subtypes across the globe, which suggests that LDI may promote successful dissemination of HIV at local geographic levels by means of increased transmission fitness.

Figure 1

α4β7 mimotope tripeptide distribution among HIV-1 V2 sequences from South America. (A) HIV-1 subtypes B and C in pediatric and adult samples (study groups). Because the number of V2 F1 subtypes was limited in our dataset (n = 3), it is not shown. (B) HIV-1 subtypes B, C, F1, BC and BF from South America (including sequences retrieved from the Los Alamos HIV Sequence Database).

Figure 2

Line trends of LDI increase and LDV decrease over time in the HIV/AIDS epidemics among HIV-1 subtype B sequences retrieved from the Los Alamos HIV Sequence Database isolated and characterized in North America (A), South America (B) and Western Europe (C). The asterisks in all three panels refer to merging of periods 2006-2010 and >2010, due to low numbers of sequences deposited in the Los Alamos Database after 2010.