Viral reservoirs present a formidable challenge in our search for a cure of human immunodeficiency Virus (HIV) infection. It is widely known tthat combined antiretroviral medications do not access the central nervous system (CNS) at optimal levels. Recent experience with hematopoietic stem cell transplant technology highlight both the need to purge the CNS reservoir from latent HIV-infected macrophages and microglia, and the requirement for utilizing homozygous CCR5Δ32 allele in successfully curing HIV infection and progression to acquired immunodeficiency syndrome (AIDS). These developments bring into focus the need to study additional alleles that affect disease progression, neurocognitive status, and potential viral egress from the CNS.