Lessons to be Learned from Natural Control of HIV – Future Directions, Therapeutic, and Preventive Implications

David Shasha, Bruce D. Walker

Accumulating data generated from persons who naturally control HIV without the need for antiretroviral treatment has led to significant insights into the possible mechanisms of durable control of AIDS virus infection. At the center of this control is the HIV-specific CD8 T cell response, and the basis for this CD8-mediated control is gradually being revealed. Genome wide association studies coupled with HLA sequence data implicate the nature of the HLA-viral peptide interaction as the major genetic factor modulating durable control of HIV, but host genetic factors account for only around 20% of the variability in control. Other factors including specific functional characteristics of the TCR clonotypes generated in vivo, targeting of vulnerable regions of the virus that lead to fitness impairing mutations, immune exhaustion, and host restriction factors that limit HIV replication all have been shown to additionally contribute to control. Moreover, emerging data indicate that the CD8(+) T cell response may be critical for attempts to purge virus infected cells following activation of the latent reservoir, and thus lessons learned from elite controllers (ECs) are likely to impact the eradication agenda. On-going efforts are also needed to understand and address the role of immune activation in disease progression, as it becomes increasingly clear that durable immune control in ECs comes at a cost. Taken together, the research achievements in the attempt to unlock the mechanisms behind natural control of HIV will continue to be an important source of insights and ideas in the continuous search after an effective HIV vaccine, and for the attempts to achieve a sterilizing or functional cure in HIV positive patients with progressive infection.