Researcher Stories

Mechanisms of HIV Neuropathology

HIV-1 tropism in neuropathogenesis and therapy

Maria Paz Gonzalez-Perez, PhD, Assistant Professor, and Paul R. Clapham, PhD, Professor, Program in Molecular Medicine, University of Massachusetts Medical School

About 30% of untreated AIDS patients suffer severe dementias. In the era of HAART, HIV-associated dementia (HAD) and other neurocognitive issues are greatly reduced. Nevertheless, there is a continuing problem of milder neurocognitive impairments in HIV+ patients. These mild impairments may increase in severity with long term therapy, while HAD still occurs in untreated individuals and those who fail therapy. The persistence of neurocognitive issues in patients on therapy may result from the poor penetration of many current drugs into brain tissue.

Gonzalez-Perez Lab

Gonzalez-Perez Lab

Maria Paz Gonzalez-Perez, PhD, Assistant Professor, Program in Molecular Medicine, University of Massachusetts Medical School

Photo Credit: John Slonka

Maria Paz Gonzalez-Perez, PhD, Assistant Professor and Paul Clapham, PhD, Professor, in the Program in Molecular Medicine at the University of Massachusetts Medical School and their team are studying the presence of different HIV viral variants in brain tissue to better understand the neuropathogenesis of AIDS-related dementia and to elucidate the persistent viral reservoir present there. Dr. Gonzalez-Perez and Dr. Clapham's group has found HIV viral variants in the brain that are highly efficient in infecting macrophages, the main type of cells infected by HIV in the brain. These infected macrophages likely form a long term, persistent reservoir of HIV that will need to be effectively targeted to eliminate residual neurological problems. In addition, new strategies will need to be developed to completely eradicate HIV from the brain for a complete cure.

Dr. Gonzalez-Perez and Dr. Clapham's group is purifying specific cell types from HIV+ brain tissue including macrophages, T-cells and astrocytes. These enriched cell populations are being used to identify and measure the presence and extent of HIV reservoirs in patients with and without neurological problems. Their studies will also provide evidence on whether variants present in the brain are associated with drug resistance mutations. If such variants accrue drug resistance mutations in brain tissue where drugs are delivered at sub-optimal levels, they may be able to re-enter non-brain tissues, disseminating drug resistance throughout the body.

“Our research would not be possible without the use of fresh post-mortem brain tissue. We are eternally grateful to the donors who make this possible.”   

Dr. Clapham and Dr. Gonzalez-Perez’s work highlights the value of human tissue in understanding HIV pathogenesis and its importance in the development of effective treatments needed to improve patient care and eventually to eliminate HIV completely from the brain and body.

Recent Publications

Peters, P.J., Bhattacharya, J., Hibbitts, S., Dittmar, M.T., Simmons, G.S., Bell, J., Simmonds, P.S., and Clapham, P.R. (2004). Phenotype analysis of HIV-1 envelopes amplified from brain tissue of AIDS patients with neuropathology indicates the presence of envelopes with an enhanced tropism and fusigenicity for macrophages. J. Virol. 78: 6915-­6926. PMCID: PMC421670.

Peters, P.J., Sullivan, W.M., Duenas-Decamp, M.J., Bhattacharya, J., Ankghuambom, C., Brown, R., Luzuriaga, K., Bell, J., Simmonds, P., Ball, J., Clapham, P.R. (2006). Non-macrophage-tropic human immunodeficiency virus type 1 R5 envelopes predominate in blood, lymph nodes, and semen: implications for transmission and pathogenesis. J Virol. 80:6324-32. PMCID: PMC1488974.

Duenas-Decamp, M.J., Peters, P.J., Burton, D., Clapham, P.R. (2009). Determinants flanking the CD4 binding loop modulate macrophage tropism of human immunodeficiency virus type 1 R5 envelopes. J Virol. 83:2575-83. PMCID: PMC2648272.

Gonzalez-Perez, M.P., O'Connell, O.J., Lin, R., Sullivan, W.M., Bell, J., Simmonds, P., and Clapham, P.R. (2012). Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue. Retrovirology 9:20. PMCID: PMC3362761.

O'Connell, O., Repik, A., Reeves, J.D., Gonzalez-Perez, M.P., Quitadamo, B., Anton, E.D., Duenas-Decamp, M., Peters, P., Lin, R., Zolla-Pazner, S., Corti, D., Wallace, A., Wang, S., Kong, X.P., Lu, S., Clapham, P.R. (2013). Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism. J Virol. 87:187-198. PMCID: PMC3536387.

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