Background: Cellular tropism of human immunodeficiency virus (HIV-1) is closely
linked to interactions between the viral envelope glycoprotein (Env) with CD4 and chemokine receptor
family members, CCR5 and CXCR4. This interaction plays a key role in determining anatomic
sites that are infected in vivo and the cascade of early and late events that result in chronic immune
activation, immunosuppression and ultimately, AIDS. CD4+ T cells are critical to adaptive
immune responses, and their early and rapid infection in gut lamina propria and secondary lymphoid
tissues in susceptible hosts likely contributes to viral persistence and progression to disease. CD4+
macrophages are also infected, although their role in HIV-1 pathogenesis is more controversial.
Methods: Pathogenic infection by simian immunodeficiency viruses (SIV) in Asian macaques as
models of HIV-1 infection has enabled the impact of cellular tropism on pathogenesis to be directly
probed. This review will highlight examples in which experimental interventions during SIV infection
or the introduction of viral mutations have altered cellular tropism and, subsequently, pathogenesis.
Results: Alterations to the interaction of Env and its cellular receptors has been shown to result in
changes to CD4 dependence, coreceptor specificity, and viral tropism for gut CD4+ T cells and
Conclusion: Collectively, these findings have yielded novel insights into the critical role of the viral
Env and tropism as a driver of pathogenesis and host control and have helped to identify new areas
for targeted interventions in therapy and prevention of HIV-1 infection.