Abstract
BackgroundIntersubtype recombination is a powerful driving force for HIV evolution, impacting both HIV-1 diversity within an infected individual and within the global epidemic. This study examines if viral protein function/fitness is the major constraint shaping selection of recombination hotspots in replication-competent HIV-1 progeny. A better understanding of the interplay between viral protein structure-function and recombination may provide insights into both vaccine design and drug development.ResultsIn vitro HIV-1 dual infections were used to recombine subtypes A and D isolates and examine breakpoints in the Env glycoproteins. The entire env genes of 21 A/D recombinants with breakpoints in gp120 were non-functional when cloned into the laboratory strain, NL4-3. Likewise, cloning of A/D gp120 coding regions also produced dead viruses with non-functional Envs. 4/9 replication-competent viruses with functional Env’s were obtained when just the V1-V5 regions of these same A/D recombinants (i.e. same A/D breakpoints as above) were cloned into NL4-3.ConclusionThese findings on functional A/D Env recombinants combined with structural models of Env suggest a conserved interplay between the C1 domain with C5 domain of gp120 and extracellular domain of gp41. Models also reveal a co-evolution within C1, C5, and ecto-gp41 domains which might explain the paucity of intersubtype recombination in the gp120 V1-V5 regions, despite their hypervariability. At least HIV-1 A/D intersubtype recombination in gp120 may result in a C1 from one subtype incompatible with a C5/gp41 from another subtype.
Highlights
Intersubtype recombination is a powerful driving force for HIV evolution, impacting both Human immunodeficiency virus type 1 (HIV-1) diversity within an infected individual and within the global epidemic
Even though Peripheral blood mononuclear cells (PBMCs) are more relevant in generating recombinants similar in HIV patients, based on our previous experience, the infection efficiency of HIV in PBMCs is much lower than in U87.CD4.CCR5 cell line resulting in very low levels of recombinant genomes, and the sites of intersubtype recombination was similar in U87 cells and PBMCs [1, 2, 30, 31]
Seven A/D gp120 recombinants were excluded based on premature stop codons or frameshift in the envelope open reading frame (ORF) or duplicates with the same unique breakpoint
Summary
Intersubtype recombination is a powerful driving force for HIV evolution, impacting both HIV-1 diversity within an infected individual and within the global epidemic. This study examines if viral protein function/ fitness is the major constraint shaping selection of recombination hotspots in replication-competent HIV-1 progeny. A better understanding of the interplay between viral protein structure-function and recombination may provide insights into both vaccine design and drug development. We have explored the functional constraints that limit intersubtype recombination in the HIV-1 env gene. These mechanistic studies on HIV-1 recombination can provide valuable insight. The HIV-1 envelope is a glycoprotein trimeric complex found on the viral surface, embedded in the membrane, and composed of the gp120 subunit spikes in a non-covalent interaction with the gp harboring the transmembrane domain. The C4 region of gp120 mediates binding to the host CD4 molecule, inducing a conformational change, and promoting interaction between gp120 C2 and V3 regions with the N
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