Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. Of the quantities that predict how quickly an untreated infection progresses, the most widely used is set-point viral load. This measure varies by orders of magnitude between infected individuals and is predictive of infectiousness and time to onset of AIDS. Host factors, predominantly linked to the immune system, are known to influence the set point, but much variation remains unexplained.

A transmission chain with heritable virulence. Individuals infected with HIV show differences in clinical progression. Untreated infections are characterized by viral loads (the viral particle density in the blood) that are relatively stable for years, but they can differ by orders of magnitude between individuals. Host factors clearly influence viral load, but viral loads have also recently been found to correlate among individuals in transmission pairs and chains. This indicates a moderate to strong influence of viral genotype on the viral load. Strikingly, this influence persists for years and across transmission events, despite intense within-host viral evolution. A transmission chain with heritable virulence. Individuals infected with HIV show differences in clinical progression. Untreated infections are characterized by viral loads (the viral particle density in the blood) that are relatively stable for years, but they can differ by orders of magnitude between individuals. Host factors clearly influence viral load, but viral loads have also recently been found to correlate among individuals in transmission pairs and chains. This indicates a moderate to strong influence of viral genotype on the viral load. Strikingly, this influence persists for years and across transmission events, despite intense within-host viral evolution.

We review recent evidence showing that HIV genotype influences the set-point viral load far more than anticipated. Our summary of published estimates suggests that 33% (95% confidence interval, 20 to 46%) of the variation is attributable to the virus. Because set-point viral load is heritable (partially controlled by virus genotype) and is linked to transmissibility, it is likely to have evolved to maintain transmission fitness and may continue to evolve in response to diverse selection pressures. These findings are unexpected and paradoxical because rapid and error-prone viral replication should favor within-host adaptation and rapidly scramble signals of viral genotype as infection progresses, rather than leaving a lasting footprint that is preserved throughout an infection and from one infection to the next in transmission chains.

We propose that resolving the paradox of heritability of set-point viral load will provide new insights into the mechanisms of HIV pathogenesis. To this end, we provide three parsimonious, testable, and nonexclusive explanatory mechanisms. The first states that HIV evolution in virulence genes is more functionally constrained than previously thought. The second proposes that virulence of HIV is mediated through the virus’s capacity to systemically activate target cells in which it can efficiently replicate. The capacity to activate would not be expected to evolve rapidly because it does not provide a specific selective advantage to virus strains that activate more cells; rather, it is an advantage shared by all viruses. The third mechanism implicates the preferential transmission of viruses that are stored in nonreplicating cells or during early infection, and the disproportionate influence on long-term pathogenesis of these early viruses.

In addition to these insights into mechanisms of pathogenesis …