cns (central nervous system) viral dynamics and cellular immunity during aids

Conditions: HIV Infections

Summary: understanding whether or not viral replication occurs in the brain during chronic untreated hiv-1 infection is of undeniable importance, and has implications for treatment and research priorities. evidence suggests that viral replication in the cns occurs at the extremes of hiv-1 disease. brain involvement has been reported during acute infection, and there is convincing evidence of cns viral replication during hiv-associated dementia (had) and advanced aids. some human and primate data suggest that viral rna and proteins may be absent from brains of some individuals with chronic untreated hiv-1 infection despite abundant proviral dna. however, the extent of viral replication in the brain is not known for most of the 42 million people worldwide living with untreated hiv-1 infection. why is viral replication in the brain such a pivotal issue? microglial cells and macrophages are primary targets for intrathecal hiv-1 replication, and this can promote neuronal injury through direct effects of gp120 and tat, and indirect induction of toxic mediators. low-grade injury over years or decades would likely be deleterious, particularly as the population ages. because treatment guidelines allow systemic hiv-1 replication to continue until cd4+ t cell counts decline considerably, antiretroviral therapy (art) is not recommended for many persons living with hiv. demonstrating replication in the brain during chronic hiv-1 infection may affect treatment strategies and encourage investigation. identifying factors that modulate intrathecal viral replication is equally important. anti-hiv-1 cytotoxic t lymphocytes (ctl) partially control systemic viral replication and delay disease progression. although available data has been provocative, the role of anti-hiv ctl in the cns has received little attention. to fill this gap we will examine relationships between intrathecal viral replication, ctl responses, and glial activation/proliferation during hiv-1 infection. these studies will be relevant not only to aids but to other inflammatory diseases of the cns as well.


Eligibility criteria:
inclusion criteria: * (all subjects in groups a1, a2 and b): * at least 18 years of age. * no more than one month of art in the past. * no art in the previous 3 months. * platelet count \>100,000 cells/mm3 on most recent determination within 60 days prior to first study lumbar puncture. * normal prothrombin time (pt) and partial thromboplastin time (ptt) on most recent determination within 60 days prior to first study lumbar puncture. * among individuals with past art experience, the ability to construct an art regimen predicted to completely suppress plasma hiv-1 rna, based on results of viral susceptibility testing that is done as a routine part of clinical practice. * plasma hiv-1 rna \>20,000 copies/ml. * additional inclusion criteria for groups a1 and a2. * group a1: * cd4+ t cell count \>200 cells/mm3. * csf hiv-1 rna \>2,000 copies/ml on screening lumbar puncture. * no history of significant allergy to beta lactam antibiotics, including penicillins and cephalosporins. * no history of allergy to vancomycin. * group a2: * cd4+ t cell count \<200 cells/mm3. * csf hiv-1 rna \>2,000 copies/ml on screening lumbar puncture. * no history of significant allergy to beta lactam antibiotics, including penicillins and cephalosporins. * no history of allergy to vancomycin. exclusion criteria: * evidence of cns opportunistic infections or space occupying lesion. * history of significant cns disorder unrelated to hiv infection such as trauma, congenital malformations or genetic disorders. * history of seizures. * as determined by the investigator, a significant active or previous history of cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, or endocrine disease(s) that would interfere with study participation. * evidence or suspicion of vascular or alzheimer's type dementias. * evidence or suspicion of parkinson's disease. * history of allergy to lidocaine. * implanted metal objects that make mri contraindicated. this may require consultation with colleagues in the vanderbilt dept. of radiology. * women who are pregnant or breastfeeding. * women with a positive pregnancy test on enrollment or prior to study drug administration. * women of childbearing potential (wocbp) who are unwilling or unable to use an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. * prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

Keywords: hiv aids cns brain affects