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The Journal of Infectious Diseases 05/2013; · 6.41 Impact Factor
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Erica Weber,
Erin E Morgan,
Jennifer E Iudicello,
Kaitlin Blackstone,
Igor Grant,
Ronald J Ellis,
Scott L Letendre, Susan Little,
Sheldon Morris,
Davey M Smith,
David J Moore,
Steven Paul Woods
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Erica Weber,
Erin E Morgan,
Jennifer E Iudicello,
Kaitlin Blackstone,
Igor Grant,
Ronald J Ellis,
Scott L Letendre, Susan Little,
Sheldon Morris,
Davey M Smith,
David J Moore,
Steven Paul Woods
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ABSTRACT: The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naive adults with median duration of infection of 75 days relative to a sample of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States, a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly fivefold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, the results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.
Journal of NeuroVirology 12/2012; · 2.31 Impact Factor
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ABSTRACT: Specific sequence changes of human immunodeficiency virus type 1 (HIV-1) in the presence of specific HLA molecules may alter the composition and processing of viral peptides, leading to immune escape. Persistence of these mutations after transmission may leave the genetic fingerprint of the transmitter's HLA profile. Here, we evaluated the associations between HLA profiles and the phylogenetic relationships of HIV sequences sampled from a cohort of recently infected individuals in San Diego, California.
We identified transmission clusters within the study cohort, using phylogenetic analysis of sampled HIV pol genotypes at a genetic distance of <1.5%. We then evaluated the association of specific HLA alleles, HLA homozygosity, HLA concordance, race and ethnicity, and mutational patterns within the clustering and nonclustering groups.
From 350 cohort participants, we identified 162 clustering individuals and 188 nonclustering individuals. We identified trends for enrichment of particular alleles within individual clusters and evidence of viral escape within those clusters. We also found that discordance of HLA alleles was significantly associated with clustering individuals.
Some transmission clusters demonstrate HLA enrichment, and viruses in these HLA-associated clusters often show evidence of escape to enriched alleles. Interestingly, HLA discordance was associated with clustering in our predominantly MSM population.
The Journal of Infectious Diseases 03/2012; 205(10):1529-33. · 6.41 Impact Factor
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Christine M Hogan,
Victor Degruttola,
Xin Sun,
Susan A Fiscus,
Carlos Del Rio,
C Bradley Hare,
Martin Markowitz,
Elizabeth Connick,
Bernard Macatangay,
Karen T Tashima,
Beatrice Kallungal,
Rob Camp,
Tia Morton,
Eric S Daar, Susan Little
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ABSTRACT: The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved.
A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group).
At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings.
Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment.
NCT00090779.
The Journal of Infectious Diseases 01/2012; 205(1):87-96. · 6.41 Impact Factor
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ABSTRACT: The interferon-inducible antiviral factor BST-2 prevents several enveloped viruses, including HIV, from escaping infected cells. The HIV protein Vpu antagonizes this host defense. Little is known about the expression of BST-2 during HIV infection in vivo and whether it can be modulated to the host's advantage. We studied the expression of BST-2 on blood cells from HIV-infected patients during the acute and chronic phases of disease as well as after antiretroviral treatment (ART). The expression of BST-2 was increased on mononuclear leukocytes, including CD4-positive T lymphocytes from HIV-positive patients, compared to that on cells of uninfected controls. The expression of BST-2 was highest during acute infection and decreased to levels similar to those of uninfected individuals after ART. Treatment of primary blood mononuclear cells in vitro with alpha interferon or with Toll-like receptor (TLR) agonists increased the expression of BST-2 to levels similar to those found during infection in vivo. The interferon-induced levels were sufficient to overcome the Vpu protein in vitro, reducing the release of wild-type HIV. These data show that BST-2 is upregulated during HIV infection, consistent with its role as an interferon-stimulated gene. The data further suggest that this upregulation is sufficient to saturate the activity of Vpu and inhibit wild-type HIV.
Journal of Virology 08/2011; 85(20):10659-68. · 5.40 Impact Factor
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ABSTRACT: Current HIV screening guidelines in the United States recommend expanding the scope of HIV screening to include routine screening in health care settings; however, this will require increased resources. Since testing of pooled samples can decrease costs, the test characteristics of pooled rapid antibody testing were determined and optimal pool sizes were estimated for populations with HIV prevalence ranging from 0.25% to 10%. Based on these results, pooled testing methods were evaluated for screening patients admitted to hospital in San Diego, California. Evaluation of pooled antibody testing on samples collected from individuals with known HIV infection found only a modest reduction in sensitivity. These false negative results were only found among samples with very low optical density readings (<0.125 by the ADVIA Centaur® HIV assay). These readings are considered as HIV negative by the ADVIA Centaur® HIV assay, and therefore likely correspond to samples collected during acute infection. Further evaluation of pooled testing of samples collected from individuals during recent infection, found that mini-pool testing of five samples detected HIV antibody in 86% of samples taken within 60 days of the initial infection and 92% of samples taken within 90 days of the initial infection. Based on estimations of optimal pool sizes for low prevalence populations, it was decided to evaluate mini-pools consisting of 10 samples to screen the study's hospitalized patients. During this evaluation, the HIV prevalence among hospitalized patients was 0.8%, and the 10 sample mini-pool testing had 100% sensitivity and specificity. Additionally, pooled testing resulted in an 84.5% reduction in the number of rapid HIV antibody tests needed, as compared to testing each sample individually. Even when incorporating the increased costs of technician time, mini-pooled tested would have resulted in a net savings of 8760 USD for the 523 samples tested in the study. Taken together, these results indicate that pooled rapid antibody testing may reduce substantially the costs for HIV screening in low prevalence populations without a loss in accuracy.
Journal of virological methods 06/2011; 174(1-2):94-8. · 2.13 Impact Factor
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David J Moore,
Scott L Letendre,
Sheldon Morris,
Anya Umlauf,
Reena Deutsch,
Davey M Smith, Susan Little,
Alexandra Rooney,
Donald R Franklin,
Ben Gouaux,
Shannon Leblanc,
Debra Rosario,
Christine Fennema-Notestine,
Robert K Heaton,
Ronald J Ellis,
J Hampton Atkinson,
Igor Grant
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ABSTRACT: We examined neurocognitive functioning among persons with acute or early HIV infection (AEH) and hypothesized that the neurocognitive performance of AEH individuals would be intermediate between HIV seronegatives (HIV-) and those with chronic HIV infection. Comprehensive neurocognitive testing was accomplished with 39 AEH, 63 chronically HIV infected, and 38 HIV- participants. All AEH participants were HIV infected for less than 1 year. Average domain deficit scores were calculated in seven neurocognitive domains. HIV-, AEH, and chronically HIV infected groups were ranked from best (rank of 1) to worst (rank of 3) in each domain. All participants received detailed substance use, neuromedical, and psychiatric evaluations and HIV infected persons provided information on antiretroviral treatment and completed laboratory evaluations including plasma and CSF viral loads. A nonparametric test of ordered alternatives (Page test), and the appropriate nonparametric follow-up test, was used to evaluate level of neuropsychological (NP) functioning across and between groups. The median duration of infection for the AEH group was 16 weeks [interquartile range, IQR: 10.3-40.7] as compared to 4.9 years [2.8-11.1] in the chronic HIV group. A Page test using ranks of average scores in the seven neurocognitive domains showed a significant monotonic trend with the best neurocognitive functioning in the HIV- group (mean rank = 1.43), intermediate neurocognitive functioning in the AEH group (mean rank = 1.71), and the worst in the chronically HIV infected (mean rank = 2.86; L statistic = 94, p < 0.01); however, post-hoc testing comparing neurocognitive impairment of each group against each of the other groups showed that the chronically infected group was significantly different from both the HIV- and AEH groups on neurocognitive performance; the AEH group was statistically indistinguishable from the HIV- group. Regression models among HIV infected participants were unable to identify significant predictors of neurocognitive performance. Neurocognitive functioning was worst among persons with chronic HIV infection. Although a significant monotonic trend existed and patterns of the data suggest the AEH individuals may fall intermediate to HIV- and chronic participants, we were not able to statistically confirm this hypothesis.
Journal of NeuroVirology 02/2011; 17(1):50-7. · 2.31 Impact Factor
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Amie L Meditz,
Samantha MaWhinney,
Amanda Allshouse,
William Feser,
Martin Markowitz, Susan Little,
Richard Hecht,
Eric S Daar,
Ann C Collier,
Joseph Margolick,
J Michael Kilby,
Jean-Pierre Routy,
Brian Conway,
John Kaldor,
Jay Levy,
Robert Schooley,
David A Cooper,
Marcus Altfeld,
Douglas Richman,
Elizabeth Connick
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ABSTRACT: It is unknown whether sex and race influence clinical outcomes following primary human immunodeficiency virus type 1 (HIV-1) infection.
Data were evaluated from an observational, multicenter, primarily North American cohort of HIV-1 seroconverters.
Of 2277 seroconverters, 5.4% were women. At enrollment, women averaged .40 log₁₀ fewer copies/mL of HIV-1 RNA (P < .001) and 66 more CD4(+) T cells/μL (P = .006) than men, controlling for age and race. Antiretroviral therapy (ART) was less likely to be initiated at any time point by nonwhite women and men compared to white men (P < .005), and by individuals from the southern United States compared to others (P = .047). Sex and race did not affect responses to ART after 6 months (P > .73). Women were 2.17-fold more likely than men to experience >1 HIV/AIDS-related event (P < .001). Nonwhite women were most likely to experience an HIV/AIDS-related event compared to all others (P = .035), after adjusting for intravenous drug use and ART. Eight years after diagnosis, >1 HIV/AIDS-related event had occurred in 78% of nonwhites and 37% of whites from the southern United States, and 24% of whites and 17% of nonwhites from other regions (P < .001).
Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States.
The Journal of Infectious Diseases 02/2011; 203(4):442-51. · 6.41 Impact Factor
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ABSTRACT: Current methods to detect intraclade HIV dual infection are poorly suited for determining its prevalence in large cohorts. To investigate the potential of ultra-deep sequencing to screen for dual infection, we compared it to bulk sequence-based synonymous mixture index and the current standard of single genome sequencing. The synonymous mixture index identified samples likely to harbor dual infection, while ultra-deep sequencing captured more intra-host viral diversity than single genome sequencing at approximately 40% of the cost and 20% of the laboratory and analysis time. The synonymous mixture index and ultra-deep sequencing are promising methods for rapid and cost-effective systematic identification of HIV dual infection.
AIDS research and human retroviruses 10/2010; 26(12):1291-8. · 2.18 Impact Factor
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ABSTRACT: In this investigation, we evaluated explanations for the unusual degree of genetic diversity in HIV populations within the sampled seminal cell and plasma compartments observed in our previous study. These analyses included clonal sequencing of HIV DNA in peripheral blood mononuclear cells, ultradeep sequencing of HIV RNA in blood plasma, human leukocyte antigen (HLA) haplotyping of previously used samples, and a BLAST screen against both a local and public repository of HIV-1 sequences, and the investigations to determine whether these observations were secondary to contamination or artifact were unsuccessful. As there are very few HIV sequences from seminal cell tissues and transmission pairs described in the literature, future studies that evaluate more transmission pairs with sampling from multiple anatomic compartments and at multiple time points will most likely be required to resolve this controversy.
Science translational medicine 09/2010; 2(50):50lr1. · 7.80 Impact Factor
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Toshiyuki Miura,
Zabrina L Brumme,
Mark A Brockman,
Pamela Rosato,
Jennifer Sela,
Chanson J Brumme,
Florencia Pereyra,
Daniel E Kaufmann,
Alicja Trocha,
Brian L Block, [......],
Elizabeth Connick,
Heiko Jessen,
Anthony D Kelleher,
Eric Rosenberg,
Martin Markowitz,
Kim Schafer,
Florin Vaida,
Aikichi Iwamoto, Susan Little,
Bruce D Walker
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ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P = 0.018). Moreover, of two HLA-B57-positive (B57(+)) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57(+) donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.
Journal of Virology 08/2010; 84(15):7581-91. · 5.40 Impact Factor
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Martin Markowitz,
Florin Vaida,
C Bradley Hare,
Daniel Boden,
Hiroshi Mohri,
Frederick M Hecht,
Robert C Kalayjian,
Ann Conrad,
Donna Mildvan,
Judith Aberg,
Christine Hogan,
J Michael Kilby,
Henry H Balfour,
Kim Schafer,
Douglas Richman, Susan Little
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ABSTRACT: Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4(+) T cell counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologic or immunologic benefit.
The Journal of Infectious Diseases 03/2010; 201(9):1298-302. · 6.41 Impact Factor
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Eric S Rosenberg,
Barney S Graham,
Ellen S Chan,
Ronald J Bosch,
Vicki Stocker,
Janine Maenza,
Martin Markowitz, Susan Little,
Paul E Sax,
Ann C Collier,
Gary Nabel,
Suzanne Saindon,
Theresa Flynn,
Daniel Kuritzkes,
Dan H Barouch
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ABSTRACT: An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099)
Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17-23 weeks after treatment discontinuation.
Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log(10) HIV-1 RNA copies/mL, respectively.
The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group.
Clinicaltrials.gov NCT00125099.
PLoS ONE 01/2010; 5(5):e10555. · 4.09 Impact Factor
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Christopher H Woelk,
Nadejda Beliakova-Bethell,
Miguel Goicoechea,
Yingdong Zhao,
Pinyi Du,
Steffney E Rought,
Jean Lozach,
Josué Pérez-Santiago,
Douglas D Richman,
Davey M Smith, Susan J Little
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ABSTRACT: To identify a pre-HAART gene expression signature in peripheral blood mononuclear cells (PBMCs) predictive of CD4 T-cell recovery during HAART in HIV-infected individuals.
This retrospective study evaluated PBMC gene expression in 24 recently HIV-infected individuals before the initiation of HAART to identify genes whose expression is predictive of CD4 T-cell recovery after 48 weeks of HAART.
The change in CD4 T-cell count (DeltaCD4) over the 48-week study period was calculated for each of the 24 participants. Twelve participants were assigned to the 'good' (DeltaCD4 > or = 200 cells/microl) and 12 to the 'poor' (DeltaCD4 < 200 cells/microl) CD4 T-cell recovery group. Gene expression profiling of the entire transcriptome using Illumina BeadChips was performed with PBMC samples obtained before HAART. Gene expression classifiers capable of predicting CD4 T-cell recovery group (good vs. poor), as well as the specific DeltaCD4 value, at week 48 were constructed using methods of Class Prediction.
The expression of 40 genes in PBMC samples taken before HAART predicted CD4 T-cell recovery group (good vs. poor) at week 48 with 100% accuracy. The expression of 22 genes predicted a specific DeltaCD4 value for each HIV-infected individual that correlated well with actual values (R = 0.82). Predicted DeltaCD4 values were also used to assign individuals to good vs. poor CD4 T-cell recovery groups with 79% accuracy.
Gene expression in PBMCs can be used as biomarkers to successfully predict disease outcomes among HIV-infected individuals treated with HAART.
AIDS (London, England) 11/2009; 24(2):217-22. · 4.91 Impact Factor
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ABSTRACT: To develop less costly methods to virologically monitor patients receiving antiretroviral therapy, we evaluated methods that use pooled blood samples and quantitative information available from viral load assays to monitor a cohort of patients on first-line antiretroviral therapy for virologic failure.
We evaluated 150 blood samples collected after 6 months of therapy from participants enrolled in a San Diego primary infection program between January 1998 and January 2007. Samples were screened for virologic failure with individual viral load testing, 10 x 10 matrix pools and minipools of five samples. For the pooled platforms (matrix and minipools), we used a search and retest algorithm based on the quantitative viral load data to resolve samples that remained ambiguous for virologic failure. Viral load thresholds were more than 500 and more than 1500 copies/ml for the matrix and more than 250 and more than 500 copies/ml for the minipool. Efficiency, accuracy and result turnaround times were evaluated.
Twenty-three percent of cohort samples were detectable at more than 50 HIV RNA copies/ml. At an algorithm threshold of more than 500 HIV RNA copies/ml, both minipool and matrix methods used less than half the number of viral load assays to screen the cohort, compared with testing samples individually. Both pooling platforms had negative predictive values of 100% for viral loads of more than 500 HIV RNA copies/ml and at least 94% for viral loads of more than 250 HIV RNA copies/ml.
In this cohort, both pooling methods improved the efficiency of virologic monitoring over individual testing with a minimal decrease in accuracy. These methods may allow for the induction and sustainability of the virologic monitoring of patients receiving antiretroviral therapy in resource-limited settings.
AIDS (London, England) 09/2009; 23(16):2151-8. · 4.91 Impact Factor
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ABSTRACT: Antiretroviral therapy in early HIV infection may enhance outcome and viral control may be better in acute versus recent infection 24 weeks after treatment interruption.
A prospective trial of treatment stratified by acute versus recent HIV-1 infection. If HIV viral load <50 copies/ml after at least 52 weeks, treatment was interrupted. If viremia rebounded, treatment and interruption were repeated. The primary endpoint was maintaining viral load less than 5000 copies/ml for 24 weeks following treatment interruption.
Of the 121 patients enrolled at 15 sites, ninety-five percent were men, median age was 34 years; 69% were white. Median viral load was higher in acute HIV-1 infection (210 000 copies/ml) than recent HIV-1 infection (43 000 copies/ml). The 73 primary endpoint patients (28 acute HIV-1 infection, 45 recent HIV-1 infection) had significantly higher baseline CD4 T-cell counts (P = 0.044) and lower viral load (P = 0.016). The primary endpoint was achieved in 29 (40%) of the 73 and in 24% of the 121 enrolled overall. There was no significant outcome difference (P = 0.81) between the acute HIV-1 infection [43%, 95% confidence interval (CI) 24-63%] and recent HIV-1 infection (38%, 95% CI 24-53%) groups. Differences after longer follow-up can not be ascertained by this trial. Baseline viral load less than 100 000/ml 22/46 (48%) compared with more than 100 000/ml, 7/27 (26%) and higher baseline CD4 immune activation predicted success.
Forty percent of patients treated during acute HIV-1 infection or recent HIV-1 infection sustained a viral load less than 5000 copies/ml after 24 weeks of treatment interruption.
AIDS (London, England) 08/2009; 23(15):1987-95. · 4.91 Impact Factor
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Hendrik Streeck,
Jonathan S Jolin,
Ying Qi,
Bader Yassine-Diab,
Randall C Johnson,
Douglas S Kwon,
Marylyn M Addo,
Chanson Brumme,
Jean-Pierre Routy, Susan Little,
Heiko K Jessen,
Anthony D Kelleher,
Frederick M Hecht,
Rafick-Pierre Sekaly,
Eric S Rosenberg,
Bruce D Walker,
Mary Carrington,
Marcus Altfeld
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ABSTRACT: Primary HIV-1 infection (PHI) is marked by a flu-like syndrome and high levels of viremia that decrease to a viral set point with the first emergence of virus-specific CD8+ T-cell responses. Here, we investigated in a large cohort of 527 subjects the immunodominance pattern of the first virus-specific cytotoxic T-lymphocyte (CTL) responses developed during PHI in comparison to CTL responses in chronic infection and demonstrated a distinct relationship between the early virus-specific CTL responses and the viral set point, as well as the slope of CD4+ T-cell decline. CTL responses during PHI followed clear hierarchical immunodominance patterns that were lost during the transition to chronic infection. Importantly, the immunodominance patterns of human immunodeficiency virus type 1 (HIV-1)-specific CTL responses detected in primary, but not in chronic, HIV-1 infection were significantly associated with the subsequent set point of viral replication. Moreover, the preservation of the initial CD8+ T-cell immunodominance patterns from the acute into the chronic phase of infection was significantly associated with slower CD4+ T-cell decline. Taken together, these data show that the specificity of the initial CTL response to HIV is critical for the subsequent control of viremia and have important implications for the rational selection of antigens for future HIV-1 vaccines.
Journal of Virology 06/2009; 83(15):7641-8. · 5.40 Impact Factor
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Steven Yukl,
Satish Pillai,
Peilin Li,
Karen Chang,
William Pasutti,
Chris Ahlgren,
Diane Havlir,
Matthew Strain,
Huldrych Günthard,
Douglas Richman,
Andrew P Rice,
Eric Daar, Susan Little,
Joseph K Wong
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ABSTRACT: The ability of HIV to establish latent infection in CD4+ lymphocytes represents a major barrier to the eradication of HIV. It is not clear what mechanisms favor latent over productive infection, but prior studies have suggested a role for the viral transcription factor Tat or its RNA target, TAR. Using samples from five individuals who were started on ART within 6 months of infection and achieved a viral load <50 (suppressed), we isolated one- and two-exon tat RNA from HIV propagated ex vivo from baseline plasma and from co-cultures of CD4+ T cells obtained at baseline and suppressed time points. Compared to virus from the baseline plasma (mostly from productively-infected CD4+ T cells), virus from the baseline and suppressed co-cultures (mostly from latently-infected cells) had more Tat variants with impaired transactivation activity. These findings suggest that impaired activity in the Tat-TAR axis may contribute to the establishment of latent infection in CD4+ T cells.
Virology 03/2009; 387(1):98-108. · 3.35 Impact Factor
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Davey M Smith,
Susanne J May,
Samantha Tweeten,
Lydia Drumright,
Mary E Pacold,
Sergei L Kosakovsky Pond,
Rick L Pesano,
Yolanda S Lie,
Douglas D Richman,
Simon D W Frost,
Christopher H Woelk, Susan J Little
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ABSTRACT: Current public health efforts often use molecular technologies to identify and contain communicable disease networks, but not for HIV. Here, we investigate how molecular epidemiology can be used to identify highly related HIV networks within a population and how voluntary contact tracing of sexual partners can be used to selectively target these networks.
We evaluated the use of HIV-1 pol sequences obtained from participants of a community-recruited cohort (n = 268) and a primary infection research cohort (n = 369) to define highly related transmission clusters and the use of contact tracing to link other individuals (n = 36) within these clusters. The presence of transmitted drug resistance was interpreted from the pol sequences (Calibrated Population Resistance v3.0).
Phylogenetic clustering was conservatively defined when the genetic distance between any two pol sequences was less than 1%, which identified 34 distinct transmission clusters within the combined community-recruited and primary infection research cohorts containing 160 individuals. Although sequences from the epidemiologically linked partners represented approximately 5% of the total sequences, they clustered with 60% of the sequences that clustered from the combined cohorts (odds ratio 21.7; P < or = 0.01). Major resistance to at least one class of antiretroviral medication was found in 19% of clustering sequences.
Phylogenetic methods can be used to identify individuals who are within highly related transmission groups, and contact tracing of epidemiologically linked partners of recently infected individuals can be used to link into previously defined transmission groups. These methods could be used to implement selectively targeted prevention interventions.
AIDS (London, England) 01/2009; 23(2):225-32. · 4.91 Impact Factor
