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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JB was supported by the Medical Research Council Precision Medicine Doctoral Training Grant (2016 to 2021; MR/N013166/1); KEA was funded by a European Research Council Starting Grant (award number 757688). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used to fit the heritability model from the Swiss HIV Cohort Study are available from the corresponding author on reasonable request. All code is available on GitHub under GPL3.0 licence.