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Biomedical subjects

Jeffrey N Martin

Publications and source records attributed to Jeffrey N Martin.

At least 19 recordsLinked to original sources
PubMed2007

Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals.

RATIONALE: Although interferon (IFN)-gamma release assays are approved for the diagnosis of latent tuberculosis infection (LTBI), limited data exist regarding their performance in HIV infection. OBJECTIVES: To compare tuberculin skin test (TST) results to the commercial IFN-gamma release assay QuantiFERON-TB Gold In-Tube (QFT) for the diagnosis of LTBI in HIV-infected adults. METHODS: A total of 294 HIV-infected subjects sampled from two San Francisco cohorts underwent TST, using 5 TU of purified protein derivative, and QFT, measuring IFN-gamma response to Mycobacterium tuberculosis-specific RD-1 antigens. MAIN RESULTS: Of 294 participants, 205 (70%) returned for an evaluable TST. Concordance between QFT and TST was 89.3% (kappa=0.37, p=0.007). However, in subjects with positive test results by either TST or QFT, only 28% (8/29) had positive test results by both modalities. TST-positive/QFT-negative discordant results were found in 5.1% of subjects and TST-negative/QFT-positive discordance in 5.6%. Indeterminate QFT results occurred in 5.1%, all due to a failure to respond to the phytohemagglutinin-positive control. Subjects with a CD4(+) count of less than 100 cells/mm(3) had a relative risk of an indeterminate result of 4.24 (95% confidence interval, 1.55-11.61; p=0.003) compared with those with a CD4(+) count of 100 or more. CONCLUSIONS: Overall concordance between QFT and TST in HIV infection was high, but agreement among subjects with positive tests by either modality was low.

Adult↗
PubMed2006

Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen.

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

Adult↗
PubMed2006

Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses.

OBJECTIVES: HIV-infected subjects are at increased risk for myocardial infarction. The mechanism of this increased risk remains unclear. Since cytomegalovirus (CMV) infection has been associated with accelerated atherosclerosis in the transplant population and immune responses against CMV may be altered by HIV disease, we hypothesized that enhanced T-cell responses against CMV would be associated with increased atherosclerosis in subjects with HIV. METHODS: We measured high-sensitivity C-reactive protein (hs-CRP), T-cell activation, CMV-specific T-cell responses, and carotid artery intima-media thickness (IMT) in 93 HIV-infected subjects and in 37 uninfected controls. RESULTS: The mean age of the HIV-infected subjects was 48 years and 85 (91%) were male. The median carotid IMT was higher in the HIV-infected group compared to the uninfected group (0.95 mm versus 0.68 mm, P < 0.001). This difference remained significant after controlling for all traditional risk factors. Compared to HIV-negative controls, HIV-infected subjects had higher median levels of hs-CRP (P = 0.05), higher levels of CD4 and CD8 T-cell activation (P < 0.0001) and higher CMV-specific interferon-gamma CD8 T-cell responses (P < 0.0001). CMV-specific T-cell responses, but not hs-CRP and T-cell activation, were independently associated with higher carotid IMT (P = 0.001). CONCLUSIONS: HIV-infected subjects had thicker carotid IMT compared to controls. While HIV patients also had higher T-cell activation, hs-CRP levels, and CMV-specific T-cell responses, only CMV-specific T-cell responses were independently associated with IMT. Accelerated atherosclerosis in HIV patients may be mediated by heightened CMV-induced immune responses.

Antibodies, Viral↗
PubMed2006

Microbial translocation is a cause of systemic immune activation in chronic HIV infection.

Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <or= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.

Animals↗
PubMed2006

Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen.

BACKGROUND: Many treatment-experienced, HIV-infected patients who have limited therapeutic options for complete viral suppression continue to receive a partially suppressive treatment regimen pending the availability of at least 2 new antiretroviral drugs. The major risk of this approach is ongoing viral evolution and the loss of future drug options. METHODS: Antiretroviral-treated subjects with incomplete viral suppression were sampled from a clinic-based cohort. Inclusion criteria were receipt of a stable treatment regimen for > or = 120 days, a plasma HIV RNA load of > 500 copies/mL, and > or = 1 resistance mutation. Phenotypic and genotypic resistance testing was performed every 4 months. RESULTS: The 106 patients who were eligible for the study had a median of 3 observations during a median of 11.3 months. An estimated 23% and 18% developed at least 1 new nucleoside analogue and 1 new protease inhibitor mutation at 1 year, respectively. An estimated 30% lost the phenotypic equivalent of 1 susceptible drug at 1 year. A lower number of total mutations at baseline was a significant predictor of developing a new nucleoside analogue mutation (P=.01). At 1 year, the probability that an existing mutation would become undetectable using population-based sequencing was 32%. There was a higher rate of change at nonresistance codons than at codons known to be associated with drug resistance. CONCLUSIONS: Heavily pretreated patients with HIV infection who remain on a partially suppressive regimen have a measurable risk of losing future drug options, particularly those patients who have few baseline mutations. Resistance mutations vary over time, which suggests that the results of any single resistance test may not be representative of all mutations selected by a given treatment regimen.

Anti-HIV Agents↗
PubMed2006

Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia.

Although CXCR4-tropic viruses are relatively uncommon among untreated human immunodeficiency virus (HIV)-infected individuals except during advanced immunodeficiency, the prevalence of CXCR4-tropic viruses among treated patients with detectable viremia is unknown. To address this issue, viral coreceptor usage was measured with a single-cycle recombinant-virus phenotypic entry assay in treatment-naive and treated HIV-infected participants with detectable viremia sampled from 2 clinic-based cohorts. Of 182 treated participants, 75 (41%) harbored dual/mixed or X4-tropic viruses, compared with 178 (18%) of the 976 treatment-naive participants (P<.001). This difference remained significant after adjustment for CD4+ T cell count and CCR5 Delta 32 genotype. Enrichment for dual/mixed/X4-tropic viruses among treated participants was largely but incompletely explained by lower pretreatment nadir CD4 + T cell counts. CCR5 inhibitors may thus be best strategically used before salvage therapy and before significant CD4 + T cell depletion.

Adult↗
PubMed2006

IL-2 production correlates with effector cell differentiation in HIV-specific CD8+ T cells.

BACKGROUND: Diminished IL-2 production and lack of effector differentiation have been reported for HIV-specific T cells. In this study, we examined the prevalence of these phenomena using 8-color cytokine flow cytometry, and tested the hypothesis that these two findings were causally related. We analyzed cytokine profiles and memory/effector phenotypes of HIV-specific and CMV-specific T cells using short-term in vitro stimulation with HIV or CMV peptide pools. Nineteen HIV-positive subjects with progressive disease and twenty healthy, HIV-negative subjects were examined. RESULTS: Among HIV-infected subjects, there were significantly fewer CD8+ IL-2+ T cells responding to HIV compared to CMV, with no significant difference in CD4+ IL-2+ T cells. The majority of CMV-specific T cells in both HIV-negative and HIV-positive subjects appeared to be terminally differentiated effector cells (CD8+ CD27- CD28- CD45RA+ or CD8+ CD27- CD28- CD45RA-). In HIV-positive subjects, the most common phenotype of HIV-specific T cells was intermediate in differentiation (CD8+ CD27+ CD28- CD45RA-). These differences were statistically significant, both as absolute cell frequencies and as percentages. There was a significant correlation between the absolute number of HIV-specific CD8+ IL-2+ T cells and HIV-specific CD8+ CD27- CD28- CD45RA+ terminal effector cells. CONCLUSION: IL-2 production from antigen-specific CD8+ T cells correlates with effector cell differentiation of those cells.

Journal Article↗
PubMed2006

The independent effect of drug resistance on T cell activation in HIV infection.

OBJECTIVE: Antiretroviral-treated individuals with drug-resistant HIV experience slower CD4 cell count declines than untreated individuals, independent of degree of viremia. As immune activation independently predicts disease progression, we hypothesized that patients with drug-resistant viremia would have less immune activation than patients with wild-type viremia, independent of plasma HIV RNA levels and that these differences would not be explained by a direct drug effect of protease inhibitors. METHODS: Percentages of activated (CD38/HLA-DR) T cells were compared between untreated participants with wild-type viremia and antiretroviral-treated participants with drug-resistant viremia, after adjusting for plasma HIV RNA levels among other factors associated with T cell activation. Changes in T cell activation were also assessed in subjects discontinuing protease inhibitors while continuing other antiretroviral medications. RESULTS: Twenty-one untreated participants with wild-type viremia and 70 antiretroviral-treated participants with drug-resistant viremia were evaluated. Relative to untreated participants, those with drug-resistant viremia had 29% fewer activated CD4 (P = 0.051) and CD8 (P = 0.012) T cells after adjustment for plasma HIV RNA levels among other factors. There was no evidence for an early change in T cell activation among 13 subjects with drug-resistant viremia interrupting protease inhibitors while continuing other antiretroviral medications, but a significant increase in T cell activation with complete or partial emergence of wild-type sequences in protease. CONCLUSIONS: Antiretroviral-treated patients with drug-resistant viremia have less T cell activation than untreated patients, independent of plasma HIV RNA level. Decreased ability of drug-resistant variants to cause T cell activation likely contributes to slower CD4 cell count declines among patients with drug-resistant viremia.

ADP-ribosyl Cyclase 1↗
PubMed2006

Variations in plasmacytoid dendritic cell (PDC) and myeloid dendritic cell (MDC) levels in HIV-infected subjects on and off antiretroviral therapy.

Plasmacytoid and myeloid dendritic cells are reduced in AIDS patients. The number of these circulating cells was assessed cross-sectionally and longitudinally in 27 uninfected and 72 HIV-infected subjects on and off antiretroviral therapy. The plasmacytoid dendritic cell numbers were significantly reduced in the HIV-infected subjects compared to controls (p < 0.001). This reduction correlated directly with CD4+ cell counts (p < 0.001) and inversely with viral load (p < 0.001). These associations were found to a lesser degree for the myeloid dendritic cells. Intra-assay variability of these dendritic cell counts was < 10%. Antiretroviral therapy significantly increased plasmacytoid dendritic cell (p < 0.001) and CD4+ cell (p = 0.05) counts at 8 months by 76.9% and 19%, respectively. The plasmacytoid dendritic cell levels responded more readily to viral load increases and decreases than CD4+ cells. Circulating plasmacytoid dendritic cells may provide important additional information about immune function in HIV-infected subjects receiving or not receiving antiretroviral therapy.

Adult↗
PubMed2006

Continued evolution in gp41 after interruption of enfuvirtide in subjects with advanced HIV type 1 disease.

Careful examination of viral dynamics during antiretroviral treatment can provide important insights into HIV pathogenesis. We examined viral evolution during and after enfuvirtide (T-20) treatment with an objective of defining the characteristics of viral evolution during advanced HIV immunodeficiency. Specifically, we examined the viral quasispecies from nine patients who experienced incomplete viral suppression on an enfuvirtide-based regimen, and who subsequently interrupted enfuvirtide while remaining on a stable optimized background regimen (enfuvirtide "partial treatment interruption"). On average, eight clones were sequenced from three time points: pre-enfuvirtide, post-enfuvirtide failure, and post-enfuvirtide interruption. We utilized a Bayesian hierarchical phylogenetic model to assess the evolutionary relatedness of the virus that emerged over time. In most subjects, interruption of enfuvirtide was associated with continued viral evolution as enfuvirtide mutations waned; in no subject did we find clear evidence supporting the reemergence of archived wild-type variants (Bayes factor=30.2, p=0.01). Evidence supporting ongoing viral evolution was particularly strong in subjects whose virus remained diverse or became more diverse during enfuvirtide therapy. In contrast to observations when all drugs are interrupted, loss of resistance during enfuvirtide interruption is most likely due to ongoing viral evolution (and back-mutation), rather than emergence of an archived virus.

Bayes Theorem↗
PubMed2006

Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis.

OBJECTIVES: To study the dynamics of enfuvirtide (T-20) resistance development in HIV-1-infected subjects. PATIENTS AND METHODS: Clonal analysis of gp41 sequences was performed on serial samples obtained from HIV-1-infected subjects with early virologic failure of T-20-based regimens. RESULTS: Enfuvirtide resistance mutations at codons 36 to 45 in the first heptad repeat of gp41 emerged within 2 weeks in most subjects and were associated with the return of plasma HIV-1 RNA level toward baseline by weeks 4 to 8. Mutations at codons 36 (G36E, G36D, or G36S) and 38 (V38A, V38G, or V38M) were the most commonly detected resistance mutations at week 2. Mutations at codons 40 (Q40H) and 43 (N43D) were more prevalent at week 4 than at week 2 and seemed to emerge more slowly than mutations at codons 36 and 38. CONCLUSIONS: The rapid emergence of mutations associated with T-20 resistance in the absence of a fully suppressive antiretroviral regimen demonstrates a low genetic barrier to resistance and underscores the importance of combining T-20 with other active drugs when constructing regimens for highly treatment-experienced patients.

Amino Acid Sequence↗
PubMed2006

Neutralizing antibody responses against autologous and heterologous viruses in acute versus chronic human immunodeficiency virus (HIV) infection: evidence for a constraint on the ability of HIV to completely evade neutralizing antibody responses.

Acute human immunodeficiency virus (HIV) infection is associated with the rapid development of neutralization escape mutations. The degree to which viral evolution persists in chronic infection has not been well characterized, nor is it clear if all patients develop high-level neutralization antibody escape. We therefore measured neutralizing antibody responses against autologous and heterologous viruses in a cohort of acutely and chronically infected subjects (n = 65). Neutralizing antibody responses against both autologous virus and heterologous viruses were lower among individuals with acute infection than among those with chronic infection. Among chronically infected individuals, there was a negative correlation between the level of neutralizing antibodies against autologous virus and the level of viremia. In contrast, there was a positive correlation between the level of neutralizing antibodies against a panel of heterologous viruses and the level of viremia. Viral evolution, as defined by the presence of higher neutralizing titers directed against earlier viruses than against contemporaneous viruses, was evident for subjects with recent infection but absent for those with chronic infection. In summary, neutralizing antibody responses against contemporaneous autologous viruses are absent in early HIV infection but can be detected at low levels in chronic infection, particularly among those controlling HIV in the absence of therapy. HIV replication either directly or indirectly drives the production of increasing levels of antibodies that cross-neutralize heterologous primary isolates. Collectively, these observations indicate that although HIV continuously drives the production of neutralizing antibodies, there may be limits to the capacity of the virus to evolve continuously in response to these antibodies. These observations also suggest that the neutralizing antibody response may contribute to the long-term control of HIV in some patients while protecting against HIV superinfection in most patients.

Acute Disease↗
PubMed2005

High-risk sexual behavior in adults with genotypically proven antiretroviral-resistant HIV infection.

BACKGROUND: The substantial frequency of drug resistance in persons recently infected with HIV implies exposure among HIV-uninfected individuals to HIV-infected persons with drug-resistant virus. Although there is an increasing emphasis on understanding high-risk behavior among HIV-infected patients, little work has focused on those with drug-resistant virus. METHODS: We examined antiretroviral-treated patients with drug resistance in the Study of the Consequences of the Protease Inhibitor Era, a clinic-based cohort of HIV-infected adults. Sexual behavior was ascertained by self-administered questionnaire. Genotypic antiretroviral resistance testing was performed on isolates from participants with a plasma HIV RNA level > or =100 copies/mL. RESULTS: Among 279 participants on antiretroviral therapy, 168 (60%) had genotypic resistance to at least 1 drug. In those with drug resistance, 27% of men who have sex with men (MSM) and 11% of heterosexual men and women reported at least 1 episode of unprotected penile-anal or penile-vaginal intercourse in the previous 4 months; 17% of MSM and 6% of heterosexual participants reported unprotected intercourse with an HIV-uninfected or status unknown partner. In a multivariable model of predictors of unprotected anal or vaginal intercourse with an HIV-uninfected or status unknown partner, there was strong evidence for an effect of younger age, depression, and sildenafil use and moderate evidence for frequent alcohol use. CONCLUSIONS: Among HIV-infected patients with drug-resistant viremia, there is a substantial prevalence of high-risk sex with HIV-uninfected partners. The presence of definable risk factors for unsafe sex suggests a role for targeted rather than broad intervention, particularly when resources are limited.

Adult↗
PubMed2005

Seroconversion following nonoccupational postexposure prophylaxis against HIV.

BACKGROUND: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. CONCLUSIONS: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Anti-HIV Agents↗
PubMed2005

The relationship between nucleoside analogue treatment duration, insulin resistance, and fasting arterialized lactate level in patients with HIV infection.

BACKGROUND: Treatment with nucleoside reverse-transcriptase inhibitors (NRTIs) is associated with hyperlactatemia, presumably as a result of NRTI-induced mitochondrial toxicity. We examined the association of NRTI treatment duration and lactate level in human immunodeficiency virus (HIV)-infected patients and assessed the relationship of treatment duration and lactate level with insulin resistance. METHODS: Fasting arterialized venous lactate levels, routine blood chemistry findings, insulin resistance (determined by homeostasis model assessment [HOMA-IR]), percentage of body fat (determined by dual-energy radiographic absorptiometry), and detailed histories of antiretroviral therapy were obtained for 95 HIV-infected individuals. The independent association of NRTI treatment duration and lactate level was examined using multivariable linear regression. RESULTS: Among 95 subjects with a mean age (+/- standard deviation [SD]) of 44 +/- 8 years), 95% had NRTI exposure, with current NRTI use in 83%. The mean (+/- SD) lactate level was 1.24 +/- 0.46 mmol/L (6% had a lactate level > 2 mmol/L). Longer duration of NRTI use was positively associated with lactate level (beta = 0.047; P < .01), as were age, duration of protease inhibitor treatment, and HOMA-IR. Female sex and percentage of body fat were negatively associated with lactate level. After adjustment for age, sex, diabetes, percentage of body fat, and duration of protease inhibitor therapy, an increased duration of NRTI therapy remained significantly associated with lactate level (beta = 0.035; P = .04). However, the addition of HOMA-IR to the adjusted model attenuated the relation between duration of NRTI therapy and lactate level (beta = 0.024; P = .14), whereas HOMA-IR was significantly associated with lactate level (beta = 0.206; P < .01). Furthermore, HOMA-IR was also associated with NRTI treatment duration in adjusted analyses. CONCLUSION: NRTI treatment duration was independently associated with higher lactate level, but this relationship was attenuated after adjusting for HOMA-IR. These data raise the possibility that insulin resistance may be an additional mechanism through which NRTI therapy is related to lactate level.

Adult↗
PubMed2005

Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection.

BACKGROUND: Many antiretroviral-treated human immunodeficiency virus (HIV)-infected patients experience sustained immunologic and virologic benefit despite the presence of multidrug-resistant HIV. We hypothesized that the use of simplified regimens could maintain treatment benefit while preventing viral evolution and reducing drug-related toxicity and costs. METHODS: We conducted a 48-week nonrandomized study of adults with multidrug-resistant HIV type 1 infection. Subjects interrupted protease inhibitor (PI) (n=18), reverse-transcriptase inhibitor (RTI) (n=6), or nonnucleoside RTI (NNRTI) (n=6) treatment. RESULTS: At study entry, subjects had a median reduction in HIV RNA levels of 1.2 log10 copies/mL relative to pretreatment levels. Interruption of PI treatment was associated with stable HIV RNA levels (mean change per week, +0.005 log10 copies/mL; P=.36). PI mutations waned and replicative capacity and HIV RNA levels increased after long-term observation. HIV RNA levels also remained stable in subjects interrupting NNRTI treatment. In contrast, all subjects who interrupted RTI treatment exhibited immediate increases in HIV RNA levels, and most exhibited a subsequent loss of the M184V mutation. CONCLUSIONS: These data indicate that nucleoside analogues often exert continued antiviral activity in the setting of drug-resistance mutations and that both nucleoside analogues and PIs can select for drug-resistance mutations that reduce viral fitness. These observations support the evaluation of treatment strategies aimed at maintaining the treatment benefit of therapy while reducing drug exposure.

Anti-Retroviral Agents↗
PubMed2005

Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment.

The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy ("controllers"), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia ("noncontrollers"). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2(+) IFN-gamma(+)) CD4(+) T cells. The presence of HIV-specific CD4(+) IL-2(+) T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2(+) IFN-gamma(+) CD4(+) T cells. Measures of immune activation were lower in all CD8(+) T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2(+) and IFN-gamma(+) CD4(+) T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy.

Adult↗