Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe...

Untreated HIV-positive (HIV-1⁺) individuals frequently suffer from HIV-associated neurocognitive disorders (HAND), with about 30% of AIDS patients suffering severe HIV-associated dementias (HADs). Antiretroviral therapy has greatly reduced the incidence of HAND and HAD. However, there is a continuing problem of milder neurocognitive impairments in treated HIV⁺ patients that may be increasing with long-term therapy. In the present study, we investigated whether envelope (env) genes could be amplified from proviral DNA or RNA derived from brain tissue of 12 individuals with normal neurology or minor neurological conditions (N/MC individuals). The tropism and characteristics of the brain-derived Envs were then investigated and compared to those of Envs derived from immune tissue. We showed that (i) macrophage-tropic R5 Envs could be detected in the brain tissue of 4/12 N/MC individuals, (ii) macrophage-tropic Envs in brain tissue formed compartmentalized clusters distinct from non-macrophage-tropic (non-mac-tropic) Envs recovered from the spleen or brain, (iii) the evidence was consistent with active viral expression by macrophage-tropic variants in the brain tissue of some individuals, and (iv) Envs from immune tissue of the N/MC individuals were nearly all tightly non-mac-tropic, contrasting with previous data for neuro-AIDS patients where immune tissue Envs mediated a range of macrophage infectivities, from background levels to modest infection, with a small number of Envs from some patients mediating high macrophage infection levels. In summary, the data presented here show that compartmentalized and active macrophage-tropic HIV-1 variants are present in the brain tissue of individuals before neurological disease becomes overt or serious.IMPORTANCE The detection of highly compartmentalized macrophage-tropic R5 Envs in the brain tissue of HIV patients without serious neurological disease is consistent with their emergence from a viral population already established there, perhaps from early disease. The detection of active macrophage-tropic virus expression, and probably replication, indicates that antiretroviral drugs with optimal penetration through the blood-brain barrier should be considered even for patients without neurological disease (neuro-disease). Finally, our data are consistent with the brain forming a sanctuary site for latent virus and low-level viral replication in the absence of neuro-disease.