Reconciling founder variant multiplicity of HIV-1 infection with the rate of CD4 ⁺ decline

Three quarters of new HIV-1 infections are reported to be initiated by a single genetic variant. Infections initiated by multiple variants have been linked with higher recipient set point viral loads (SpVL) and a faster rate of CD4 ⁺ T cell decline, indicative of a worse clinical prognosis if left untreated. These findings have not been universally replicated, however, and a mechanism through which multiple variants might lead to a worse prognosis is yet to be elucidated. In this study, we first summarised the existing evidence for this ‘dose response’ phenomenon for HIV-1, and quantified how likely we are to observe a true difference in set point viral load between multiple and single variant infections. Next, we considered whether the association between higher SpVL and multiple variant infection could exist in the absence of a causal mechanism. For a fixed diversity, high transmitter SpVL could simultaneously lead to high recipient SpVL through the inheritance of a ‘high virulence’ genotype and a greater probability that recipient infection is initiated by multiple genetic variants. Nonetheless, a high transmitter SpVL also shortens the duration of infection, consequently reducing the likelihood of the higher SpVL individual transmitting and restricting the overall accumulation of viral diversity. We combined data-driven models of transmission, heritability and HIV-1 disease progression to test whether an association between multiple variant infection and clinical progression is expected. First, we found that we are unlikely to record a significant difference in SpVL between multiple and single variant infections, at frequencies of multiple variant infections consistent with empirical observations. Second, we found that we would not expect multiple variant infections to lead to higher SpVL or faster CD4 ⁺ T cell decline without a causal mechanism. Specifically, the probability that infection is initiated by multiple variants is greatest at the highest transmitter SpVLs, yet the relationship between transmitter and recipient SpVL is relatively weak. This finding supports the hypothesis that a within-patient causal mechanism is required to explain the association of multiple variant infection with higher viral loads and faster CD4 ⁺ T cell decline. Further investigation into events happening during and just after transmission are required to enhance our understanding of this association.