Cindy Christopherson

Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1- infected long-term survivors

HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.

Effect of Influenza Vaccination on Viral Replication and Immune Response in Persons Infected with Human Immunodeficiency Virus Receiving Potent Antiretroviral Therapy

Nineteen patients infected with human immunodeficiency virus (HIV) with varying levels of viral suppression achieved with antiretroviral therapy were evaluated to determine whether trivalent influenza vaccine activated HIV replication. Humoral immune responses and CD4+ lymphocyte subsets were compared in 5 HIV-uninfected vaccinated subjects. Transient elevations of plasma HIV RNA levels (76-89 copies/mL) appeared within 2 weeks in 3 of 11 patients with <50 copies/mL at baseline. Sustained elevation in HIV plasma RNA was observed in 7 of 8 patients with baseline HIV RNA of >50 copies/mL. HIV DNA decreased in patients with <400 RNA copies/mL at baseline and showed an HIV RNA increase after vaccination (n=8) when compared with 8 patients with <50 copies/mL at baseline who lacked viral response to vaccination. Concurrent decreases in proviral DNA and memory phenotype CD4+ cells in association with increased plasma HIV RNA after vaccination in patients with <400 RNA copies/mL at baseline suggest that in vivo mobilization of the latently infected cell reservoir may occur during potent antiretroviral therapy.

Multiple measures of HIV burden in blood and tissue are correlated with each other but not with clinical parameters in aviremic subjects.

Objectives: To determine the levels of residual HIV DNA and RNA in blood and gut reservoirs in aviremic patients, assess correlations among compartmental measurements of HIV burden, and evaluate association with clinical parameters. Design: Cross-sectional analysis of baseline data only, on 40 patients enrolled in phase II study evaluating efficacy of autologous gene-modified CD4+ and CD8+ T cells. All patients were on stable antiretroviral regimen with undetectable plasma HIV RNA (< 50 copies/ml). Methods: Measurements repeatedly performed over 8–12 weeks pre-intervention: blood HIV DNA, analysis of rectal mucosa-associated lymphoid tissue for both HIV RNA and HIV DNA, and quantitative co-culture of HIV from CD8-depleted peripheral blood mononuclear cells (PBMC). Results: Quantifiable levels of HIV detected in compartments despite undetectable levels of plasma HIV RNA: HIV co-culture of PBMC (88%), blood HIV DNA (95%), rectal biopsy HIV DNA (95%), rectal biopsy HIV RNA (65%). A significant correlation existed among various measures of HIV burden (HIV co-culture, blood HIV DNA, rectal biopsy HIV RNA and DNA) but not between assays and clinical parameters [duration of highly active antiretroviral therapy (HAART), type of HAART]. All assays had comparable or less variability than in plasma viral load assays; HIV co-culture had the highest coefficient of variability whereas the blood HIV DNA assay had the lowest and was considered the most reliable assay. Conclusions: The data support safety, feasibility and high compliance of quantifying reservoirs of residual HIV in treated subjects with undetectable plasma HIV RNA. Lack of correlation between levels of HIV in residual reservoirs and duration of HAART suggests treatment-mediated viral suppression alone does not lead to reproducible decay in HIV reservoirs.

HIV mediates a productive infection of the brain.

BACKGROUND Approximately one quarter of patients with AIDS develop severe cognitive deficits called HIV-associated dementia complex. There is some controversy regarding the importance of viral load and distribution in mediating this neurologic disease. OBJECTIVE Brain HIV proviral and RNA loads were compared to define the molecular nature of HIV infection of the brain. METHOD Neuropathologic examination was performed on brains from 10 autopsies of patients with AIDS that had short post-mortem intervals and no evidence of opportunistic infection. Viral DNA and RNA were extracted and quantified from multiple brain regions. These findings were compared with triple-label immunofluorescence for viral and cell markers. RESULTS Brains with histopathologic evidence of HIV encephalitis contained abundant HIV RNA and DNA. Regions without productive HIV infection showed minimal proviral load. By immunocytochemistry, only brain macrophages/microglia double labeled for viral proteins. CONCLUSIONS HIV mediates a productive infection of brain macrophages/microglia. There was no evidence supporting the hypothesis of substantial neuronal or macroglial infection, or evidence of substantial proviral burden prior to the development of productive infection.

Prognostic Value of Baseline Human Immunodeficiency Virus Type 1 DNA Measurement for Disease Progression in Patients Receiving Nucleoside Therapy

Human immunodeficiency virus (HIV) type 1 DNA assay data were obtained at baseline from 111 HIV-1-positive subjects who were treated with nucleosides. Higher baseline DNA level, HIV-1 RNA level, and infectious titer were comparably associated with an increased hazard of disease progression (each P<.03). Only DNA level was significantly associated with survival (adjusted hazard ratio for 1 log(10) higher level, 3.99; 95% confidence interval, 1.44-11.09; P=.008).

Persistence of Human Immunodeficiency Virus (HIV) Type 1 DNA in Peripheral Blood Despite Prolonged Suppression of Plasma HIV-1 RNA in Children

Human immunodeficiency virus (HIV) type 1 DNA in peripheral blood mononuclear cells (PBMC) was quantified in 31 children who received efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors for > or =2 years and in whom undetectable plasma HIV-1 RNA levels (< 50 copies/mL) were sustained, to determine the usefulness of HIV-1 DNA as a marker of virus suppression. The median baseline HIV-1 DNA level was 750 copies/10(6) PBMC. After initiation of highly active antiretroviral therapy (HAART), HIV-1 DNA levels decreased gradually, reaching a plateau from week 80 through week 104 (median HIV-1 DNA level, 263 copies/10(6) PBMC). Children who had plasma HIV-1 RNA levels < 50 copies/mL after receiving HAART for 8 weeks (n=16) had persistently lower quantities of intracellular HIV-1 DNA than children whose HIV-1 RNA levels reached < 50 copies/mL after 8 weeks of HAART (n=15). The median half-life for intracellular HIV-1 DNA was 60 weeks. Thus, despite prolonged maintenance of undetectable levels of plasma HIV-1 RNA, HIV-1 DNA remains detectable in PBMC of children and may be a useful marker of further virus suppression.

Polio vaccine samples not linked to AIDS

It has been suggested that chimpanzee kidney cultures may have been used in the preparation of oral polio vaccine stocks used in Africa during the late 1950s, and so could have introduced the primate precursor of the immunodeficiency virus HIV-1 into humans. Here we analyse frozen samples of the suspect vaccine by using the polymerase chain reaction (PCR) to amplify any HIV-1-related nucleic acids or chimpanzee mitochondrial DNA that might be present, but we have failed to detect either. Our findings do not support the hypothesis that HIV-1 was introduced by oral vaccination against poliovirus.