Host genetic factors are thought to contribute to the interindividual differences in the control of HIV replication. The aim of the present investigation was to determine whether genes encoding GM and KM allotypes—genetic markers of immunoglobulin γ and κ chains, respectively—and those encoding Fcgamma receptor (FcγR) IIa and IIIa are associated with the host control of HIV replication. A case-control design was employed amongst HIV-infected subjects, with a group that spontaneously controlled HIV replication (“controllers”) as cases (n=73) and those who did not control replication, as controls (n=100). Genotyping was done by PCR-RFLP, direct DNA sequencing, and TaqMan® genotyping assays. In Caucasian Americans, certain combinations of FcγR and GM genotypes were differentially distributed between controllers and non-controllers. Among the non-carriers of FcγRIIa arginine allele, GM21 non-carriers had over seven-fold greater odds of being controllers than the carriers of this allele (OR=7.47). These GM determinants also interacted with FcγRIIIa alleles. Among the carriers of the FcγRIIIa valine allele, GM21 non-carriers had over three-fold greater odds of being controllers than the carriers of this allele (OR=3.26). These results show epistatic interactions of genes on chromosomes 14 (GM) and 1 (FcγR) in influencing the control of HIV replication.
GM allotypes; KM allotypes; FcγR; ADCC; HIV
Although combination antiretroviral therapy can dramatically reduce the circulating viral load in those infected with HIV, replication-competent virus persists. To eliminate the need for indefinite treatment, there is growing interest in creating a functional HIV-resistant immune system through the use of gene-modified hematopoietic stem cells (HSC). Proof-of-concept for this approach has been provided in the instance of an HIV-infected adult transplanted with allogeneic stem cells from a donor lacking the HIV co-receptor, CCR5. Here, we review this and other strategies for HSC-based gene therapy for HIV disease.
Although, single tablet regimen (STR) efavirenz, emtricibine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) may be appealing in HIV infected persons who are at high risk for non-adherence, the degree to which this simplified formulation affects adherence is not known. The virologic effectiveness of this STR in a potentially non-adherent population remains a concern, given the rapid selection of drug-resistance seen with these drugs. We performed a prospective observational study assessing adherence and virologic response to EFV/FTC/TDF STR among a cohort of homeless and marginally housed individuals. We compared adherence and viral suppression to historical controls followed in the same cohort. Adherence was higher in EFV/FTC/TDF STR regimen compared to non-one-pill once daily therapy (p=0.0060) after controlling for multiple confounders. Viral suppression (HIV RNA <50 c/ml) was greater in EFV/FTC/TDF STR than non-one pill daily regimens (69.2% vs 46.5%; p=0.02), but there was no difference in viral suppression after controlling for adherence. Once daily EFV/TNF/FTC STR appears to be a reasonable option for individuals with multiple barriers to adherence. Randomized clinical trials addressing various therapeutic strategies for this patient population are needed.
Endothelial progenitor cells (EPCs) are involved in the endothelium repair. Low circulating EPC levels are predictive of cardiovascular events in HIV-negative subjects. The impact of HIV infection on EPCs, and the role of EPCs in HIV-associated cardiovascular disease, is not known. We hypothesized that circulating EPCs would be inversely associated with carotid artery intima-media thickness (c-IMT) changes in HIV-infected subjects.
EPCs (CD34+/KDR+, CD133+/KDR+ and CD34+/CD133+/KDR+) were defined retrospectively by flow cytometry in cryopreserved peripheral blood mononuclear cells collected longitudinally from 66 chronic HIV-infected subjects and cross-sectionally from 50 at-risk HIV-negative subjects. The HIV-infected subjects participated in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort, were receiving antiretroviral therapy (59/66) and had two sequential measurements of c-IMT 1 year apart. Two distinct groups of HIV-infected subjects were identified a priori: rapid c-IMT progressors (subjects with rapid c-IMT progression, n=13, Δc-IMT>0.2 mm) and slow c-IMT progressors (subjects with slow or no c-IMT progression, n=53, Δc-IMT<0.2 mm).
Although cryopreservation reduced sensitivity of detection, EPC frequency in HIV-infected subjects was still significantly higher compared to at-risk HIV-negative subjects (CD34+/KDR+; P=0.01) and correlated positively with CD4+ T-cell count (CD34+/KDR+, r=0.27; P=0.03). No association was found between the change of EPC frequencies over time (ΔEPC) and Δc-IMT or between EPC frequencies and c-IMT or Δc-IMT.
The lack of an association between EPCs and c-IMT in our cohort does not support HIV-associated reductions in EPC frequency as a cause of accelerated atherosclerosis.
Many human immunodeficiency virus (HIV) infected individuals suffer from persistent immune activation. Chronic inflammation and immune dysregulation have been associated with an increased risk of age-related diseases even among patients on highly active antiretroviral therapy. The factors leading to immune activation are complex, but have been hypothesized to include persistent viral replication with cellular death as well as microbial translocation across the gastrointestinal tract. Both processes may trigger innate immune responses since many native molecules released from dying cells are similar in structure to pathogen associated molecular patterns. These damage associated molecular patterns include mitochondrial DNA and formylated peptides. We hypothesized that circulating mitochondrial nucleic acid could serve as a biomarker for HIV-associated cell death and drive innate immune activation in infected individuals. We developed a quantitative polymerase chain reaction assay for plasma mitochondrial DNA and validated it on normal blood donors. We then measured mitochondrial DNA levels in acute and chronic HIV infection. While the assay proved to be accurate with a robust dynamic range, we did not find a significant association between HIV disease status and circulating mitochondrial DNA. We did, however, observe a negative correlation between age and plasma mitochondrial DNA levels in individuals with well-controlled HIV.
Although early initiation of antiretroviral therapy in HIV-infected patients after a diagnosis of Pneumocystis pneumonia increased after ACTG 5164 (7.4%–50.0%), a subsequent implementation and dissemination initiative optimized uptake of early antiretroviral therapy as clinically routine (50.0%–80.3%).
Background. Diffusion, dissemination, and implementation of scientific evidence into routine clinical practice is not well understood. The Adult AIDS Clinical Trials Group (ACTG) Protocol 5164 showed that early antiretroviral therapy (ART; ie, within 14 days) after diagnosis of an opportunistic infection improved clinical outcomes, compared with later initiation. Subsequently, the San Francisco General Hospital (SFGH) HIV/AIDS Service performed the SFGH 5164 Initiative to disseminate and implement the findings of ACTG 5164.
Methods. We evaluated patients who received a diagnosis of Pneumocystis jirovecii pneumonia (PCP) from 1 January 2001 through 30 March 2011. Survival analyses were used to assess changes in the time to initiation of ART after PCP, and logistic regression was used to evaluate changes in the odds of early ART (ie, within 14 days) because of ACTG 5164 and SFGH 5164 Initiative.
Results. Among 162 patients, the adjusted hazard of ART initiation increased by 3.05 (95% confidence interval [CI], 1.86–5.02) after ACTG 5164 and by 4.89 (95% CI, 2.76–8.67) after the SFGH Initiative, compared with before ACTG 5164. When compared with before ACTG 5164, the proportion of patients who received ART within the 14 days after PCP diagnosis increased from 7.4% to 50.0% (P < .001) after ACTG 5164 and from 50.0% to 83.0% (P = .02) after the SFGH 5164 Initiative.
Conclusions. Diffusion of findings from of a randomized trial changed practice at an academic medical center, but dissemination and implementation efforts were required to establish early ART at acceptable levels. Early ART initiation can be achieved in real-world patient populations.
Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional viral load measures and time-updated CD4+ T-lymphocyte count in antiretroviral therapy-treated patients suggesting cumulative human immunodeficiency virus replication causes harm independent of its effect on the degree of immunodeficiency.
Background. Cross-sectional plasma human immunodeficiency virus (HIV) viral load (VL) measures have proven invaluable for clinical and research purposes. However, cross-sectional VL measures fail to capture cumulative plasma HIV burden longitudinally. We evaluated the cumulative effect of exposure to HIV replication on mortality following initiation of combination antiretroviral therapy (ART).
Methods. We included treatment-naive HIV-infected patients starting ART from 2000 to 2008 at 8 Center for AIDS Research Network of Integrated Clinical Systems sites. Viremia copy-years, a time-varying measure of cumulative plasma HIV exposure, were determined for each patient using the area under the VL curve. Multivariable Cox models were used to evaluate the independent association of viremia copy-years for all-cause mortality.
Results. Among 2027 patients contributing 6579 person-years of follow-up, the median viremia copy-years was 5.3 log10 copy × y/mL (interquartile range: 4.9–6.3 log10 copy × y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log10 copy × y/mL; 95% confidence interval [CI], 1.51–2.18 per log10 copy × y/mL), 24-week VL (1.74 per log10 copies/mL; 95% CI, 1.48–2.04 per log10 copies/mL), and most recent VL (HR = 1.89 per log10 copies/mL; 95% CI: 1.63–2.20 per log10 copies/mL) were associated with increased mortality. When simultaneously evaluating VL measures and controlling for other covariates, viremia copy-years increased mortality risk (HR = 1.44 per log10 copy × y/mL; 95% CI, 1.07–1.94 per log10 copy × y/mL), whereas no cross-sectional VL measure was independently associated with mortality.
Conclusions. Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional VL measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of immunodeficiency.
To assess whether T cell activation independently predicts the extent of CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART).
Prospective cohort study
HIV-infected adults starting ART and achieving a plasma HIV RNA level (VL) <400 copies/ml by month 6 were sampled from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara, Uganda. CD4 count, VL, and the % activated (CD38+HLA-DR+) T cells were measured every 3 months.
Of 451 HIV-infected Ugandans starting ART, most were women (70%) with median pre-ART values: age, 34 years; CD4 count, 135 cells/mm3; and VL, 5.1 log10 copies/ml. Of these, 93% achieved a VL<400 c/ml by month 6 and were followed for a median of 24 months, with 8% lost to follow up at 3 years. Higher pre-ART CD8+ T cell activation was associated with diminished CD4 recovery after year 1, after adjustment for pre-ART CD4 count, VL, and gender (P=0.017). Thirty-four participants died, 15 after month 6. Each 10 percentage-point increase in activated CD8+ T cells at month 6 of suppressive ART was associated with a 1.6-fold increased hazard of subsequent death after adjusting for pre-therapy CD4 count (P=0.048).
Higher pre-ART CD8+ T cell activation independently predicts slower CD4+ T cell recovery and higher persistent CD8+ T cell activation during ART-mediated viral suppression independently predicts increased mortality among HIV-infected Ugandans. Novel therapeutic strategies aimed at preventing or reversing immune activation during ART are needed in this setting.
HIV; Uganda; Sub-Saharan Africa; T cell activation; Antiretroviral Therapy; Mortality
To define the effect of antiretroviral therapy (ART) on activation of T cells in cerebrospinal fluid (CSF) and blood, and interactions of this activation with CSF HIV-1 RNA concentrations.
Cross-sectional analysis of 14 HIV-negative subjects and 123 neuroasymptomatic HIV-1–infected subjects divided into 3 groups: not on ART (termed “offs”), on ART with plasma HIV-1 RNA >500 copies/mL (“failures”), and on ART with plasma HIV-1 RNA ≤500 copies/mL (“successes”). T-cell activation was measured by coexpression of CD38 and human leukocyte antigen DR (HLA-DR). Other measurements included CSF neopterin and white blood cell (WBC) counts.
CD8 T-cell activation in CSF and blood was highly correlated across all subjects and was highest in the offs, lower in the failures, and lower still in the successes. While CD8 activation was reduced in failures compared to offs across the range of plasma HIV-1, it maintained a coincident relation to CSF HIV-1 in both viremic groups. In addition to correlation with CSF HIV-1 concentrations, CD8 activation in blood and CSF correlated with CSF WBCs and CSF neopterin. Multivariate analysis confirmed the association of blood CD8 T-cell activation, along with plasma HIV-1 RNA and CSF neopterin, with CSF HIV-1 RNA levels.
The similarity of CD8 T-cell activation in blood and CSF suggests these cells move from blood to CSF with only minor changes in CD38/HLA-DR expression. Differences in the relation of CD8 activation to HIV-1 concentrations in the blood and CSF in the 2 viremic groups suggest that changes in immune activation not only modulate CSF HIV-1 replication but also contribute to CSF treatment effects. The magnitude of systemic HIV-1 infection and intrathecal macrophage activation are also important determinants of CSF HIV-1 RNA levels.
activation; antiretroviral therapy; cerebrospinal fluid (CSF); HIV-1; T lymphocytes
Although untreated human immunodeficiency virus (HIV)–infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.
We compared percentages of activated (CD38+HLA-DR+) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.
Although the median CD4+ cell count in controllers was 727 cells/mm3, 3 (10%) had CD4+ cell counts <350 cells/mm3 and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4+ and CD8+ cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8+ cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4+ and CD8+ T cell activation was associated with lower CD4+ cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8+ T cell activation (P = .039).
HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4+ T cell loss even without measurable viremia.
Background & Aims
Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis, by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes.
In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein (I-FABP), and interleukin (IL)-6 by ELISA, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment.
Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, I-FABP (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and IL-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for AST, P=.002 for ferritin) and fibrosis (P<.0001 for gamma-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for alpha-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively).
LPS-induced local and systemic inflammation are associated with cirrhosis and predict progression to end-stage liver disease in patients with HBV or HCV infection.
Microbial translocation; soluble CD14; hepatitis; intestinal fatty acid binding protein; chronic liver disease; histology; immune response; microbiota
Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter-region GTn microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation, and lower levels of inflammation-associated viral replication in HIV-infected subjects. Healthy donors (n=20) with shorter GTn repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) (r= −0.38, p=0.05). The presence of fewer GTn repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r= −0.41, p=0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r= −0.36, p=0.04). In African-Americans, but not Caucasians, greater GTn repeats were correlated with higher soluble CD14 (sCD14) levels during highly active antiretroviral therapy (HAART) (r= 0.38, p=0.007) as well as higher mean viral load off-therapy (r= 0.24, p=0.04). These data demonstrate that the HO-1 GTn microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.
Heme oxygenase-1; microsatellite; polymorphism; HIV; soluble CD14; monocytes
Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts.
Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995–August 2009. Parametric survival models identified factors associated with tuberculosis occurrence.
Results. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131–333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk.
Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.
The aging process affects all aspects of the immune system, particularly the T cells. The immune system in older individuals is often characterized by lower T cell numbers, lower naive/memory T cell ratios, and lower T cell diversity. Most measures of inflammation increase with age. Why this happens, and why there is so much person-to-person variability in these changes, is not known. In this issue of the JCI, Sauce and colleagues show that removal of the thymus during infancy results in premature onset of many of these age-associated changes to the immune system (see the related article beginning on page 3070). The effect of thymectomy was particularly notable in those individuals who acquired CMV infection. Data from this study, as well as data from other observational settings, suggest that reduced thymic function and persistent viral infections combine to accelerate a decline in immunologic function.
HIV disease is associated with increased arterial stiffness, which may be related to inflammation provoked by HIV-related immune perturbation. We assessed the association of T cell markers of immune activation and immunosenescence with carotid artery stiffness among HIV-infected women.
Among 114 HIV-infected and 43 HIV-uninfected women, we measured CD4+ and CD8+ T cell populations expressing activation (CD38+HLA-DR+) and senescence (CD28-CD57+) markers. We then related these measures of immune status with parameters of carotid artery stiffness, including decreased distensibility, and increased Young’s elastic modulus, as assessed by B-mode ultrasound.
HIV infection was associated with increased CD4+ T cell activation, CD8+ T cell activation and CD8+ T cell senescence. Among HIV-infected women, adjusted for age, HIV medications, and vascular risk factors, higher CD4+CD38+HLA-DR+ T cell frequency was associated with decreased carotid artery distensibility (β= −2.00, 95% confidence interval [CI]= −3.86,−0.14, P=0.04) and increased Young’s modulus (β=1.00, 95% CI=0.03,1.97, P=0.04). These associations were affected little by further adjustment for CD4+ T cell count and viral load. Among HIV-infected women, higher frequencies of immunosenescent T cells, including CD4+CD28-CD57+ and CD8+CD28-CD57+ T cells, were also associated with decreased arterial distensibility. Among HIV-uninfected women, frequencies of activated or senescent T cells were not significantly associated with measures of carotid stiffness.
T cell activation and senescence are associated with arterial stiffness, suggesting that pro-inflammatory populations of T cells may produce functional or structural vascular changes in HIV-infected women.
Background. Elevated immune activation persists during treated human immunodeficiency virus (HIV) infection and is associated with blunted CD4 recovery and premature mortality, but its causes remain incompletely characterized. We hypothesized that asymptomatic cytomegalovirus (CMV) replication might contribute to immune activation in this setting.
Methods. Thirty antiretroviral therapy–treated HIV-infected CMV-seropositive participants with CD4 counts <350 cells/mm3 were randomized to receive valganciclovir 900 mg daily or placebo for 8 weeks, followed by an additional 4-week observation period. The primary outcome was the week 8 change in percentage of activated (CD38+ HLA-DR+) CD8+ T cells.
Results. Fourteen participants were randomized to valganciclovir and 16 to placebo. Most participants (21 [70%] of 30) had plasma HIV RNA levels <75 copies/mL. The median CD4 count was 190 (IQR: 134–232) cells/mm3, and 12 (40%) of 30 had detectable CMV DNA in saliva, plasma, or semen at baseline. CMV DNA continued to be detectable at weeks 4–12 in 7 (44%) of 16 placebo-treated participants, but in none of the valganciclovir-treated participants (P = .007). Valganciclovir-treated participants had significantly greater reductions in CD8 activation at weeks 8 (P = .03) and 12 (P = .02) than did placebo-treated participants. These trends were significant even among those with undetectable plasma HIV RNA levels.
Conclusions. CMV (and/or other herpesvirus) replication is a significant cause of immune activation in HIV-infected individuals with incomplete antiretroviral therapy–mediated CD4+ T cell recovery.
Clinical Trials Registration. NCT00264290.
Gut-associated lymphoid tissue (GALT) is a major site of HIV replication and CD4+ T cell depletion. Furthermore, microbial translocation facilitated by mucosal damage likely contributes to the generalized immune activation observed in HIV infection. Regulatory T cells (Treg) help maintain homeostasis and suppress harmful immune activation during infection; however, in the case of persistent viral infections such as HIV, their role is less clear. Although a number of studies have examined Treg in blood during chronic infection, few have explored Treg in the gastrointestinal mucosa. For this study, paired blood and rectal biopsy samples were obtained from 12 HIV noncontrollers (viral load of >10,000 copies/ml plasma), 10 HIV controllers (viral load of <500 copies/ml plasma for more than 5 years), and 12 HIV seronegative control subjects. Noncontrollers had significantly higher percentages of Treg in rectal mononuclear cells (RMNC), but not in blood, compared to seronegative subjects (P = 0.001) or HIV controllers (P = 0.002). Mucosal Treg positively correlated with viral load (P = 0.01) and expression of immune activation markers by CD4+ (P = 0.01) and CD8+ (P = 0.07) T cells. Suppression assays indicated that mucosal and peripheral Treg of noncontrollers and controllers maintained their capacity to suppress non-Treg proliferation to a similar extent as Treg from seronegative subjects. Together, these findings reveal that rather than experiencing depletion, mucosal Treg frequency is enhanced during chronic HIV infection and is positively correlated with viral load and immune activation. Moreover, mucosal Treg maintain their suppressive ability during chronic HIV infection, potentially contributing to diminished HIV-specific T cell responses and viral persistence.
Steven Deeks discusses a new study that investigates the prevalence and clinical implications of transmitted minority drug-resistant HIV variants.
Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain.
Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model.
Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001).
Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.
Background. 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.
Methods. Thirty treated subjects with CD4+ T cell counts of <350 cells/mm3 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).
Results. 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.
Conclusions. Low-level viremia is not likely to be a significant cause of suboptimal CD4+ T cell gains during HIV treatment.
Clinical Trials Registration. NCT00631449.
We observed an independent association between vitamin D insufficiency and higher carotid intima-media thickness in a cross-sectional analysis of 139 HIV-infected persons. If confirmed, these findings support a clinical trial of vitamin D supplementation to reduce cardiovascular events in HIV-infected persons.
Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.
Methods and Results
We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.
Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)
Clinical Trial Registration
URL: http://clinicaltrials.gov. Unique identifier: NCT01519141
AIDS; carotid arteries; inflammation; atherosclerosis
Background. Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown.
Methods. This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples.
Results. Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2–16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4+ T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer.
Conclusions. sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.
Among HIV controllers, higher activated and HIV-specific CD4+ T cell frequencies were strongly associated with a greater burden of pro-viral DNA, suggesting that the very immune response helping control viral replication may be contributing to viral persistence.
Background. Human immunodeficiency virus (HIV)–-infected individuals maintaining plasma HIV RNA levels <75 copies/mL in the absence of therapy (“HIV controllers”) often maintain high HIV-specific T cell responses, which likely contribute to the control of viral replication. Despite robust immune responses, these individuals never eradicate HIV infection. We hypothesized that HIV-specific CD4+ T cells might serve as target cells for HIV, contributing to viral persistence in this setting.
Methods. We measured frequencies of activated (CD38+ HLA-DR+) and HIV Gag-specific CD4+ and CD8+ T cells and plasma- and cell-associated levels of HIV RNA and DNA in a cohort of 38 HIV controllers.
Results. Although there was no evidence of a relationship between the extent of low-level viremia and the frequency of either activated or HIV-specific CD4+ T cells, controllers with higher HIV-specific CD4+ T cell frequencies had higher cell-associated HIV DNA levels (ρ = 0.53; P = .019). Higher activated CD4+ T cell frequencies were also associated with higher levels of cell-associated DNA (P = .027) and RNA (P = .0096). However, there was no evidence of a relationship between cell-associated HIV RNA or DNA levels and HIV-specific CD8+ T cell frequencies.
Conclusions. These data support a model in which strong HIV-specific CD4+ T cell responses in HIV controllers, while contributing to a potent adaptive immune response, may also contribute to viral persistence, preventing the natural eradication of HIV infection.