HIV-1 and the central nervous system: HIV-1 enters the CNS and causes HIV-1-associated neurocognitive disorders (HAND) ranging from minor cognitive/motor disorders to severe dementia. In the brain, HIV-1 productively infects microglia (brain-resident macrophages) and perivascular macrophages, which express low levels of the primary receptor for HIV-1, CD4. Microglia are very long-lived cells with extremely low turnover that support viral replication for extended periods of time, and it has been hypothesized that HIV-1 may adapt in vivo to replication in microglial cells.

Our laboratory has a long-term interest in the phenotypic characterization of HIV-1 primary isolates/envelope glycoproteins derived from CNS and peripheral autopsy tissues of HIV-1-positive individuals with and without neurological disease. Using a combination of virology, cell and molecular biology, and biochemical techniques, we investigate CD4 and co-receptor requirements, envelope conformation, sensitivity to various inhibitors and binding to receptors, with the goal of increasing our understanding of the process of in vivo HIV-1 adaptation to replication in the CNS. We have contributed to the characterization of macrophage tropism and neurotropism of HIV-1, describing that brain-derived envelopes require lower levels of CD4 to efficiently mediate fusion and infection in primary target cells, thereby acquiring the capacity to infect macrophages and microglia, and concomitantly acquire a particular conformation that affects their sensitivity to entry and fusion inhibitors, and their susceptibility to be recognized by certain types of antibodies.

Schematic depiction of HIV neuroinvasion and syncytia formation (González-Scarano and Martín-García, Nature Reviews Immunology 2005; 5:69-81).

Our laboratory is also interested in evaluating the relationship between neurotropism and neurotoxicity, since we are now able to directly compare the pathogenic effects of paired viruses, as well as their envelope glycoproteins in various forms, from CNS and peripheral tissues. We plan to study the potential direct mechanisms involved in HIV-1 neurotoxicity and bystander or indirect mechanisms, to determine their contribution to HIV neuropathogenesis and potentially identify new therapeutic targets.

An accelerated aging in the HIV-1-infected population has been described. Cellular senescence has been described in multiple cell types and usually accompanies tissue dysfunction during aging. The aging of the immune system (or immunosenescence) has been linked to cellular senescence in T and B lymphocytes, but little is known regarding monocyte/macrophage lineage cells. In the CNS, cellular dysfunction compatible with a senescence phenotype has been associated with initiation and progression of neurodegenerative disorders, but cellular senescence has not been described in microglia. We have been studying the potential to develop cellular senescence in macrophages and microglia, both in the context of HIV-1 infection and under other types of cellular stress. It is apparent that HIV-1 infection induces macrophage and microglia senescence, through both direct and indirect mechanisms. We are interested in defining the macrophage and microglia senescence phenotype and their potential contribution to HAND. We also want to investigate potential therapeutic interventions that could help prevent and/or reverse their functional decline associated with HIV-1 infection and with normal aging.

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Selected Publications (See all Julio Martin-Garcia's publications in PubMed.)

"Induction of a Senescence-Like Phenotype in Cultured Human Fetal Microglia During HIV-1 Infection"
Chen NC, Partridge AT, Tuzer F, Cohen J, Nacarelli T, Navas-Martín S, Sell C, Torres C, Martín-García J
J Gerontol A Biol Sci Med Sci.. doi: 10.1093/gerona/gly022. [Epub ahead of print] PubMed PMID: 29415134, Feb 5, 2018

"Fate of microglia during HIV-1 infection: From activation to senescence?"
Chen NC, Partridge AT, Sell C, Torres C, Martín-García J
Glia;65(3):431-446. doi: 10.1002/glia.23081. Epub 2016 Nov 26. Review. PubMed PMID: 27888531; PubMed Central PMCID: PMC5263094, Mar 2017

"Hepatitis C virus core protein enhances HIV-1 replication in human macrophages through TLR2, JNK, and MEK1/2-dependent upregulation of TNF-α and IL-6"
Swaminathan G, Pascual D, Rival G, Perales-Linares R, Martin-Garcia J, Navas-Martin S
FEBS Lett.;588(18):3501-10. doi: 10.1016/j.febslet.2014.08.009. Epub 2014 Aug 14. PubMed PMID: 25131930; PubMed Central PMCID: PMC4166524, Sep 17, 2014

"Interplay between microRNAs, Toll-like receptors, and HIV-1: potential implications in HIV-1 replication and chronic immune activation"
Swaminathan G, Navas-Martín S, Martín-García J
Discov Med.;18(97):15-27. Review. PubMed PMID: 25091485, Jul-Aug, 2014

"MicroRNAs and HIV-1 infection: antiviral activities and beyond"
Swaminathan G, Navas-Martín S, Martín-García J
J Mol Biol.;426(6):1178-97. doi: 10.1016/j.jmb.2013.12.017. Epub 2013 Dec 25. Review. PubMed PMID: 24370931, Mar 20, 2014

"RNA viruses and microRNAs: challenging discoveries for the 21st century"
Swaminathan G, Martin-Garcia J, Navas-Martin S
Physiol Genomics.;45(22):1035-48. doi: 10.1152/physiolgenomics.00112.2013. Epub 2013 Sep 17. Review. PubMed PMID: 24046280; PubMed Central PMCID: PMC3841790, Nov 15, 2013

"A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages"
G Swaminathan, F Rossi, LJ Sierra, A Gupta, S Navas-Martín, and J Martín-García. 
PLoS Pathogens, 8:e1002937, doi:10.1371/journal.ppat.1002937; 2012

"Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 Capsid"
S Kortagere,N Madani, MK Mankowski, A Schön, I Zentner, G Swaminathan, A Princiotto, K Anthony, A Oza, LJ Sierra, SR Passic, X Wang, DM Jones, E Stavale, FC Krebs, J Martín-García
Journal of Virology, Antimicrobial Agents and Chemotherapy. 86:8472-8481, 2012

"Antiviral breadth and combination potential of peptide triazole HIV-1 entry inhibitors"
K McFadden, P Fletcher, F Rossi, F Kantharaju, M Umashankara, V Pirrone, S Rajagopal, H Gopi, FC Krebs, J Martín-García, RJ Shattock, and IM Chaiken. 
Antimicrobial Agents and Chemotherapy 56: 1073-1080, 2012

"The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors"
F. Rossi, B. Querido, M. Nimmagadda, S. Cocklin, S. Navas-Martín, and J Martín-García
Retrovirology, 5: 89, 2008

"Broad-spectrum anti-HIV potential of a peptide HIV-1 entry inhibitor"
S. Cocklin, H. Gopi, B. Querido, M. Nimmagadda, S. Kuriakose, C. Cicala, S. Ajith, S. Baxter, J. Arthos, J. Martín-García, and I.M Chaiken
Journal of Virology, 81: 3645-3648, 2007

"HIV-1 tropism for the central nervous system: brain-derived envelope glycoproteins with lower CD4-dependence and reduced sensitivity to a fusion inhibitor"
J. Martín-García, W. Cao, A. Varela-Rohena, M.L. Plassmeyer, and F. González-Scarano
Virology, 346: 169-179, 2006

"Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology"
M.F. Chen, S. Westmoreland, E.V. Ryzhova, J. Martín-García, S.S. Soldan, A. Lackner, and F. González-Scarano
Journal of Neurovirology, 12: 73-89, 2006

"Interaction with CD4 and antibodies to CD4-induced epitopes of the envelope gp120 from a microglia-adapted human immunodeficiency virus type 1 isolate"
J. Martín-García, S. Cocklin, I.M. Chaiken, and F. González-Scarano
Journal of Virology, 79: 6703-6713, 2005

"The neuropathogenesis of AIDS"
F. González-Scarano and J Martín-García
Nature Reviews Immunology, 5: 69-81, 2005

"Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a microglia-adapted human immunodeficiency virus type 1 and its parental isolate"
J. Martín-García, C.C. LaBranche, and F. González-Scarano
Journal of Virology, 75: 3568-3580, 2001