Background: It is commonly accepted that the brain acts as a sanctuary for HIV because of the currently prescribed antiretroviral drugs having limited access to the brain. P-glycoprotein efflux in the blood-brain barrier (BBB) is known to limit the effectiveness and dissipation of drugs into the brain, and as a consequence sub-therapeutic concentrations of antiretroviral drugs are found in the brain. Such sub-therapeutic concentrations at least theoretically should facilitate the development of resistance to HAART or may lead to independently evolving virodemes due to differential selection pressure imposed by drug(s). To examine whether this occurs in vivo, a detailed analysis of drug resistance patterns in diverse areas of the autopsied brain from 16 HIV-1-infected patients (pts) receiving HAART was conducted.

Methods: Post-mortem brain tissues were obtained from the Manhattan, Los Angeles, and Texas Brain Banks. These were derived from diverse areas of the CNS (frontal, temporal, parietal and occipital lobes, caudate body and nucleus, choroid plexus, putamen, cerebellum, periventricular white matter, anterior hippocampus and corpus collosum, etc) from HIV pts with and without dementia who received HAART. A 1,278 bp PCR fragment encompassing the reverse transcriptase and Protease regions was amplified from brain tissues. The PCR products were cloned in PGEM-2T vector and analysed for primary, secondary resistance and non-canonical mutations and interpreted using the Stanford Resistance Database (SF).

Results: The most notable and unique feature was the region-specific distribution of primary drug resistance mutations to RT, protease or both inhibitors in diverse areas of the brain. A similar or more pronounced pattern of segregation of secondary resistance mutations and a number of non-canonical mutations was also observed.

Conclusions: Independent evolution of primary, secondary drug resistance mutations and non-canonical mutations in diverse areas of the brain with region-specific accretion of primary resistance mutations. This segregation of viral populations in diverse brain regions demonstrates poor and perhaps differential penetration of HAART. This may encourage the development of HIV in regions of the brain through a milieu of sub-therapeutic drug concentrations. This phenomenon may further be accentuated by the varied tropism of HIV variants arising as a consequence of selection pressures imposed on HIV in vivo.