Rebecca Hoh

University of California, San Francisco, San Francisco, CA, United States

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Publications (59)397.16 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl ("non-controllers", n = 42), those with undetectable viral loads on ART ("ART-suppressed", n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28-CD27-CD45RA+/-CCR7-) T cell subpopulations persisted despite ART and minimal changes were noted in naïve T cell frequencies over time. Increased number of CD8+CD28- T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4∶CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN-γ. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4∶CD8 ratios remained significantly decreased and naïve T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments.
    PLoS ONE 01/2014; 9(1):e85613. · 3.53 Impact Factor
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    ABSTRACT: Background. Transcriptionally silent HIV-1 DNA persists in resting memory CD4(+) T cells despite antiretroviral therapy. In a primary cell model, the anti-alcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4(+) T cells at concentrations achieved in vivo. Methods. We conducted a single-arm pilot study to evaluate whether 500&emsp14;mg of disulfiram administered daily for 14&emsp14;days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4(+) T cells. Findings. Disulfiram was safe and well tolerated. There was high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (+1.16-fold change, 95% confidence interval (CI), .70-1.92-fold, P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (+1.53-fold, 95% CI, .88-2.69-fold, P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the post-dosing period (95% CI, 1.03-3.43-fold, P = .04). In a post-hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals with immediate post-dose sampling (HIV-1 RNA increase +2.96-fold, 95% CI, 1.29-6.81-fold, P = .01, n = 6). Interpretation. Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.
    Clinical Infectious Diseases 12/2013; · 9.37 Impact Factor
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    ABSTRACT: Quantitative humoral profiling of recent samples from an HIV-infected adult who was cured following a delta32/delta32 CCR5 stem cell transplant in 2007 revealed no antibodies against p24, matrix, nucleocapsid, integrase, protease and gp120, but low levels of antibodies against reverse transcriptase, tat and gp41. Antibody levels to these HIV proteins persisted at high and stable levels in most non-controllers, elite controllers and antiretroviral-treated subjects, but a rare subset of controllers had low levels of antibodies against matrix, reverse transcriptase, integrase and/or protease. Comprehensive HIV antibody profiles may prove useful for monitoring curative interventions.
    The Journal of Infectious Diseases 11/2013; · 5.85 Impact Factor
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    ABSTRACT: The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4(+) T cells [CD45RO(+)/CD27((+/-))]. The HIV-1 infection frequency of CD4(+) T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4-12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4-12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.
    Proceedings of the National Academy of Sciences 11/2013; · 9.81 Impact Factor
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    ABSTRACT: Several host-encoded antiviral factors suppress HIV-1 replication in a cell-autonomous fashion in vitro. The relevance of these defenses to the control of HIV-1 in vivo remains to be elucidated. We hypothesized that cellular restriction of HIV-1 replication plays a significant role in the observed suppression of HIV-1 in "elite controllers", individuals who maintain undetectable levels of viremia in the absence of antiretroviral therapy (ART). We comprehensively compared the expression levels of 34 host restriction factors and cellular activation levels in CD4+ T cells and sorted T cell subsets between elite controllers, HIV-1-infected (untreated) non-controllers, ART-suppressed, and uninfected individuals. Expression of schlafen 11, a codon usage-based inhibitor of HIV-1 protein synthesis, was significantly elevated in CD4+ T cells from elite controllers as compared to both non-controllers (p=0.048) and ART-suppressed individuals (p=0.024), with this effect most apparent in central memory CD4+ T cells. Schlafen 11 expression levels were comparable between controllers and uninfected individuals. Cumulative restriction factor expression was positively correlated with CD4+ T cell activation (r2=0.597, p<0.0001), viral load (r2=0.34, p=0.015), and expression of ISG15 (r2=0.73, p<0.0001), a marker of interferon exposure. APOBEC3C, APOBEC3D, CTR9, TRIM26, and TRIM32 were elevated in controllers with respect to ART-suppressed individuals, while levels were comparable to uninfected individuals and non-controllers. Host restriction factor expression typically scales with cellular activation levels. However, the elevated mRNA and protein expression of schlafen 11, despite low activation and viral load, violates the global pattern and may be a signature characteristic of HIV-1 elite control.
    Retrovirology 10/2013; 10(1):106. · 5.66 Impact Factor
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    ABSTRACT: The study of HIV-infected "controllers" who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of "elite" controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov NCT01025427).
    PLoS Pathogens 10/2013; 9(10):e1003691. · 8.14 Impact Factor
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    ABSTRACT: HIV-infected controllers have provided novel insights into mechanisms of viral control. We investigated the degree to which HIV DNA and RNA are present in gut-associated lymphoid tissue (GALT) of controllers. Cross-sectional cohort study. Colorectal biopsy pieces were obtained from five untreated noncontrollers, five ART-suppressed patients, and nine untreated controllers. Rectal HIV DNA was lower in controllers (median 496 copies/10 CD4 T cells) than in untreated noncontrollers (117483 copies/10 CD4 T cells, P = 0.001) and ART-suppressed patients (6116 copies/10 CD4 T cells, P = 0.004). Similarly, rectal HIV RNA was lower in controllers (19 copies/10 CD4 T cells) than in noncontrollers (15210 copies/10 CD4 T cells, P = 0.001) and ART-suppressed patients (1625 copies/10 CD4 T cells, P = 0.0599). Rectal HIV RNA/DNA ratios were not statistically different between the three groups. Despite being able to maintain very low plasma HIV RNA levels in the absence of antiretroviral therapy (ART), HIV-infected controllers have readily measurable levels of HIV DNA and RNA in GALT. As expected, controllers had lower rectal HIV DNA and RNA compared with untreated noncontrollers and ART-suppressed individuals. Compared with the mechanisms of 'natural' viral control of controllers, long-term ART does not reduce the total HIV reservoir to the level of controllers.
    AIDS (London, England) 09/2013; 27(14):2255-60. · 4.91 Impact Factor
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    ABSTRACT: Background. The degree to which HIV continues to replicate during antiretroviral therapy (ART) is controversial. We conducted a randomized, double-blind, placebo-controlled study to assess whether raltegravir intensification reduces low-level viral replication, as defined by an increase in 2-long terminal repeat (2-LTR) circles.Methods. Thirty-one ART-suppressed subjects with plasma HIV RNA <40 copies/mL and CD4+ T cell count ≥350 cells/mm(3) for ≥1 year were randomized to receive raltegravir 400 mg twice daily or placebo for 24 weeks. 2-LTR circles were analyzed by droplet digital PCR at weeks 0, 1, 2, and 8.Results. Median duration of ART suppression was 3.8 years. The raltegravir group had a significant increase in 2-LTR circles compared to the placebo group. The week 1 to 0 ratio was 8.8-fold higher (p=0.0025) and the week 2 to 0 ratio was 5.7-fold higher (p=0.023) in the raltegravir vs. placebo group. Intensification also led to a statistically significant decrease in D-dimer compared to placebo (p=0.045).Conclusions. Raltegravir intensification resulted in a rapid increase in 2-LTR circles in a proportion of subjects, indicating that low-level viral replication persists in some individuals even after long-term ART. Intensification also reduced D-dimer, a coagulation biomarker that is predictive of morbidity/mortality in treated HIV.
    The Journal of Infectious Diseases 08/2013; · 5.85 Impact Factor
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    ABSTRACT: HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4 T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4 T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4 T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.
    PLoS Pathogens 02/2013; 9(2):e1003174. · 8.14 Impact Factor
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    ABSTRACT: Background. Studies aimed at defining the association between host immune responses and human immunodeficiency virus (HIV) persistence during therapy are necessary to develop new strategies for cure. Methods. We performed a comprehensive assessment of ultrasensitive plasma HIV RNA levels, cell-associated HIV RNA levels, proviral HIV DNA levels, and T cell immunophenotyping in a cohort of 190 subjects in whom HIV levels were suppressed by highly active antiretroviral therapy. Results. The median CD4 + T cell count was 523 cells/mm 3 , and the median duration of viral suppression was 31 months. Cell-associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4 + and CD8 + T cells expressing markers of T-cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or programmed cell death protein 1 [PD-1]) (P < .05). Having a low CD4 + T-cell count despite receipt of virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (P < .01) and higher frequencies of CD4 + T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (P < .0001). Conclusions. Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1—expressing CD4 + T cells. Treated patients with a low CD4 + T-cell count had higher frequencies of PD-1—expressing CD4 + T cells and cell-based measures of viral persistence, suggesting that HIV infection in these individuals may be more difficult to cure and may require unique interventions.
    The Journal of Infectious Diseases 01/2013; 208(1):50-56. · 5.85 Impact Factor
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    ABSTRACT: Background. Studies aimed at defining the association between host immune responses and HIV persistence during therapy are necessary to develop new strategies towards cure.Methods. We performed a comprehensive assessment of ultrasensitive plasma HIV RNA, cell-associated HIV RNA, proviral HIV DNA, and T cell immunophenotyping in a cohort of 190 HAART-suppressed subjects.Results. The median CD4+ T cell count was 523 cells/mm(3) and duration of viral suppression was 31 months. Cell-associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4+ and CD8+ T cells expressing markers of T cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or PD-1) (p<0.05). Having a low CD4+ count despite virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (p<0.01) and higher frequencies of CD4+ T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (p<0.0001).Conclusions. Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1 expressing CD4+ T cells. Treated patients with a low CD4+ count had higher frequencies of PD-1 expressing CD4+ T cells and cell-based measures of viral persistence, suggesting that these individuals may be more difficult to cure and may require unique interventions.
    The Journal of Infectious Diseases 10/2012; · 5.85 Impact Factor
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    ABSTRACT: : To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals. : Randomized, double-blinded, placebo-controlled study. : Fifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence. : At baseline, the median CD4 T-cell count was 498 cells/mm, nadir CD4 T-cell count was 191 cells/mm, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4 T-cell count and current abacavir use were associated with lower hyperemic velocity. : The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).
    JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2012; 61(3):317-25. · 4.65 Impact Factor
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    ABSTRACT: : Both protective T-cell genotypes and natural killer (NK) cell genotypes have been associated with delayed progression to AIDS and shown to be co-inherited in HIV-1-infected individuals who limit viral replication in absence of antiretroviral therapy ('controllers'). However, a comparative analysis of the genotype and function of the innate and adaptive immune compartments in HIV-1-infected controller individuals has been understudied to date. : Here, we simultaneously tested NK and T-cell function in controllers to investigate the mechanism(s) that might account for host immune control over viral replication. : We measured CD8 T-cell responses against HIV-1 utilizing overlapping 15-mer peptides spanning the HIV-1 consensus clade B Gag protein and tested NK cell degranulation and cytokine secretion against tumor target cells following interferon-α (IFNα) stimulation. : Among a cohort of 37 controllers, the presence of protective major histocompatibility complex class I human leukocyte antigen (HLA) alleles (such as HLA-B*57) was not correlated with HIV-specific CD8 responses. In contrast, the inheritance of a protective killer inhibitory receptor KIR3DL1*h/*y receptor genotype along with the corresponding HLA-Bw4*80I ligand was associated with significantly heightened target cell-induced NK degranulation and cytokine secretion following IFNα stimulation (P = 0.0201, n = 13). Interestingly, we observed a significant inverse association between the IFNα stimulated NK response to K562 cells and the HIV-specific CD8 T-cell response to Gag among elite controllers (rho = -0.8321, P = 0.0010, n = 12). : Together, these results suggest that heightened NK responses can be evidenced independently of HIV-specific T-cell responses in HIV-1-infected elite controllers.
    AIDS (London, England) 08/2012; 26(15):1869-78. · 4.91 Impact Factor
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    ABSTRACT: HIV infection results in a decrease in circulating CD4(+) T-cell and naive T-cell numbers. If such losses were associated with an erosion of T-cell receptor (TCR) repertoire diversity in the peripheral T-cell pool, this might exacerbate the state of persistent immunodeficiency. Existing methods for the analysis of the TCR repertoire have demonstrated skewed distributions of TCR genes in HIV-infected subjects but cannot directly measure TCR diversity. Here we used AmpliCot, a quantitative assay based on DNA hybridization kinetics, to measure TCR diversity in a cross-sectional comparison of 19 HIV-infected persons to 18 HIV-uninfected controls. HIV-infected persons had a 10-fold decrease in total TCR repertoire diversity in 1.5 mL of blood compared with uninfected controls, with decreased diversity correlating most closely with a lower CD4(+) T-cell percentage. Nonetheless, the TCR repertoire diversity of sort-purified T-cell subpopulations in HIV-infected and HIV-uninfected subjects was comparable. These observations suggest that the TCR repertoire diversity changes in whole blood during HIV disease progression are primarily the result of changes in the number and proportion of T-cell subpopulations and that most HIV-infected persons may retain a sufficiently diverse TCR repertoire to permit immune reconstitution with antiretroviral therapy alone, without thymopoiesis.
    Blood 02/2012; 119(15):3469-77. · 9.78 Impact Factor
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    ABSTRACT: Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size. Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for ≥ 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs). The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue. Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment. NCT00631449.
    The Journal of Infectious Diseases 04/2011; 203(7):960-8. · 5.85 Impact Factor
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    ABSTRACT: HIV infection can result in depletion of total CD4(+) T cells and naive CD8(+) T cells, and in the generation of dysfunctional effector CD8(+) T cells. In this study, we show that naive CD8(+) T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8(low) T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8(low) T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3(high)CD8(+)CD4(-) single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8(low) T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.
    Blood 02/2011; 117(7):2189-99. · 9.78 Impact Factor
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    ABSTRACT: The rates of immunologic and clinical progression are lower in patients with drug-resistant HIV compared to wild-type HIV. This difference is not fully explained by viral load. It has been argued that reductions in T cell activation and/or viral fitness might result in preserved target cells and an altered relationship between the level of viremia and the rate of CD4+ T cell loss. We tested this hypothesis over time in a cohort of patients with highly resistant HIV. Fifty-four antiretroviral-treated patients with multi-drug resistant HIV and detectable plasma HIV RNA were followed longitudinally. CD4+ T cell counts and HIV RNA levels were measured every 4 weeks and T cell activation (CD38/HLA-DR) was measured every 16 weeks. We found that the levels of CD4+ T cell activation over time were a strong independent predictor of CD4+ T cell counts while CD8+ T cell activation was more strongly associated with viremia. Using spectral analysis, we found strong evidence for oscillatory (or cyclic) behavior in CD4+ T cell counts, HIV RNA levels, and T cell activation. Each of the cell populations exhibited an oscillatory behavior with similar frequencies. Collectively, these data suggest that there may be a mechanistic link between T cell activation, CD4+ T cell counts, and viremia and lends support for the hypothesis of altered predator-prey dynamics as a possible explanation of the stability of CD4+ T cell counts in the presence of sustained multi-drug resistant viremia.
    PLoS ONE 01/2011; 6(6):e21190. · 3.53 Impact Factor
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    ABSTRACT: HAART can effectively reduce plasma HIV RNA levels to below the level of detection in most HIV-infected patients. The degree to which residual low-level viremia persists during HAART remains unclear. We identified 180 individuals (median duration of HIV infection 12 years) who had at least two consecutive plasma HIV-1 RNA levels below the level of detection (<50-75 copies/ml) while taking antiretroviral drugs; 36 of 180 had been virologically suppressed for more than 5 years. Longitudinal plasma samples that were taken from these individuals during periods of viral load suppression were selected and analyzed. The isothermal transcription-mediated amplification (TMA) (limit of detection <3.5 copies RNA/ml) assay was used to measure persistent viremia. A 'detuned' EIA assay was used to obtain quantitative HIV antibody levels. A total of 1606 TMA assays were performed on 438 specimens in 180 HAART-suppressed individuals (median 3 replicates per specimen). In the first year of viral suppression, plasma RNA levels declined significantly (P = 0.001), but after month 12 there was no evidence for a continued decline (P = 0.383). In the first year of viral suppression, HIV antibody levels also declined (P = 0.054), but after month 12 there was no evidence for a continued decline (P = 0.988). Viremia continued to decline during the first 12 months after viremia became undetectable using conventional methods, and then remained stable. HIV antibody levels also decreased in the first year of viral suppression and then remained stable. Viremia and the HIV-associated host response appear to achieve a steady-state 'set-point' during long-term combination therapy.
    AIDS (London, England) 10/2010; 24(16):2535-9. · 4.91 Impact Factor
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    ABSTRACT: A subset of HIV-infected patients, termed 'elite' viral controllers, maintain undetectable plasma HIV RNA levels in the absence of therapy. In this group, host-mediated viral control may be accompanied by chronic systemic inflammation. It is unknown whether either infection or chronic inflammation is present within the central nervous system of these individuals. Cross-sectional analysis compared cerebrospinal fluid (CSF) HIV RNA and biomarkers of intrathecal inflammation in eight controllers (plasma HIV RNA levels <50 copies/ml) with 26 HIV-uninfected individuals, 25 untreated individuals HIV-infected, viremic individuals, and 23 HIV-infected individuals with treatment-mediated viral suppression (plasma HIV RNA levels <50 copies/ml). All controllers had CSF HIV RNA levels below 2.5 copies/ml. CSF white blood cell (WBC) counts and CSF: plasma albumin ratios in the controllers were similar to those in both HIV-uninfected individuals and antiretroviral therapy-suppressed HIV-infected individuals. CSF neopterin, MCP-1, and IP-10 concentrations were also not different in the controllers from either HIV-uninfected or treated HIV-infected individuals. The character of CSF HIV infection and degree of immunoactivation in controllers is comparable to that of HIV-uninfected and antiretroviral therapy-suppressed HIV-infected individuals, but distinct from that of untreated, viremic HIV-infected individuals.
    AIDS (London, England) 03/2010; 24(7):1001-5. · 4.91 Impact Factor
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    ABSTRACT: Although integrase inhibitors are highly effective in the management of drug-resistant HIV, some patients fail to achieve durable viral suppression. The long-term consequences of integrase inhibitor failure have not been well defined. We identified 29 individuals who exhibited evidence of incomplete viral suppression on a regimen containing an integrase inhibitor (23 raltegravir, 6 elvitegravir). Before initiating the integrase inhibitor-based regimen, the median CD4 T-cell count and plasma HIV RNA levels were 62 cells/mm and 4.65 log10 copies/mL, respectively. At the first failure time-point, the most common integrase resistance pattern for subjects taking raltegravir was wild-type, followed in order of frequency by Q148H/K/R+G140S, N155H, and Y143R/H/C. The most common resistance pattern for subjects taking elvitegravir was E92Q. Long-term failure was associated with continued viral evolution, emergence of high-level phenotypic resistance, and a decrease in replicative capacity. Although wild-type failure during early integrase inhibitor failure is common, most patients eventually develop high-level phenotypic drug resistance. This resistance evolution is gradual and associated with declines in replicative capacity.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 03/2010; 54(4):389-93. · 4.65 Impact Factor

Publication Stats

3k Citations
397.16 Total Impact Points

Institutions

  • 1995–2013
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Division of Experimental Medicine
      • • Division of Cardiology
      • • Department of Neurology
      • • Gladstone Institute
      San Francisco, CA, United States
  • 2007–2011
    • University of California, Los Angeles
      • Department of Biostatistics
      Los Angeles, CA, United States
  • 2008
    • Blood Systems Research Institute
      San Francisco, California, United States
  • 2006–2008
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2005
    • Institute of Human Virology
      Maryland City, Maryland, United States
  • 1999–2003
    • University of California, Berkeley
      • Department of Nutritional Science and Toxicology
      Berkeley, California, United States