The low spike density of HIV may have evolved because of the effects of T helper cell depletion on affinity maturation

The spikes on virus surfaces bind receptors on host cells to propagate infection. High spike densities (SDs) can promote infection, but spikes are also targets of antibody-mediated immune responses. Thus, diverse evolutionary pressures can influence virus SDs. HIV’s SD is about two orders of magnitude lower than that of other viruses, a surprising feature of unknown origin. By modeling antibody evolution through affinity maturation, we find that an intermediate SD maximizes the affinity of generated antibodies. We argue that this leads most viruses to evolve high SDs. T helper cells, which are depleted during early HIV infection, play a key role in antibody evolution. We find that T helper cell depletion results in high affinity antibodies when SD is high, but not if SD is low. This special feature of HIV infection may have led to the evolution of a low SD to avoid potent immune responses early in infection.
Author summary The spike protein on the virus surface mediates its entry to the host cell and a high spike density promotes infection. HIV has a spike density that is almost two orders of magnitude lower than other viruses. This unique feature of HIV has defied explanation since it was first observed. By bringing together theory and computation, rooted in statistical mechanics, with immunology we suggest that the effects of dramatic depletion of T helper cells during HIV infection on antibody production provided an evolutionary driving force for HIV to evolve a low spike density in order to avoid potent immune responses. Additionally, we show that an intermediate spike density induces maximally potent antibody production, a result with implications for vaccine design.