HIV transmission selects for fitter viruses


Introduction: Heterosexual HIV-1 transmission is an inefficient process with rates typically reported at <1% per unprotected sexual exposure. When transmission does occur, systemic infection is typically established by a single genetic variant, taken from the swarm of genetically distinct viruses that are present in the donor. Whether that founder virus represents a chance event or was systematically favored is unclear. We present evidence that selection of the founder virus is biased toward certain genetic characteristics, with subtle clinical repercussions that may help shape the course of the epidemic.

Rationale: If transmission involves selection for viruses with favorable characteristics, then such advantages will emerge as statistical biases when viewed across many viral loci in many transmitting partners. We therefore identified 137 Zambian heterosexual transmission pairs, for whom plasma samples were available for both the donor and recipient partner soon after transmission, and compared the viral sequences obtained from each partner to identify features that predicted whether the majority amino acid observed at any particular position in the donor was transmitted. We focused our attention on two features: viral genetic characteristics known to correlate with viral fitness, and clinical features known to increase the risk of transmission. Statistical modeling indicates that the former will be favored for transmission, while the latter will nullify this relative advantage.

Results: We observed a highly significant selection bias that favors the transmission of amino acids that were predicted to confer higher fitness. These features included the frequency of the amino acid in a Zambian reference cohort, the relative advantage of the amino acid with respect to the stability of the protein, and features related to immune escape and compensation. This selection bias was markedly reduced in individuals with higher risk of infection. In particular, significantly less selection bias was observed in women and in men with genital inflammation compared to healthy men, suggesting a more permissive environment in the female than male genital tract. Consistent with this observation, transmitted viruses in women were characterized by lower predicted fitness than those in men. The presence of amino acids favored during transmission predicted which individual virus within a donor was transmitted to their partner, while chronically infected individuals with viral populations characterized by a predominance of these amino acids were more likely to transmit to their partners.

Conclusion: These data highlight the stochastic nature of transmission, while demonstrating clear selection biases that advantage fitter viruses. That such biases exist, and are tempered by certain risk factors, suggests that transmission is frequently characterized by many abortive transmission events in which some target cells are nonproductively infected. Paradoxically, by increasing the selection bias at the transmission bottleneck, reduction of susceptibility may increase the expected fitness of breakthrough viruses that manage to establish infection and may therefore worsen the prognosis for the newly infected partner.  Conversely, preventative or therapeutic approaches that weaken the virus may reduce overall transmission rates via a mechanism that is independent from the quantity of circulating virus, and may therefore provide long-term benefits even upon breakthrough infection.

One Sentence Summary: HIV transmission selects for viruses with high in vivo fitness, especially among males lacking ulcers or inflammation.

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Publication Date: Jul 2014