Asymptomatic HIV-infected Subjects Research Articles

The CD8+ T Cell Noncytotoxic Antiviral Responses.

The CD8+ T cell noncytotoxic antiviral response (CNAR) was discovered during studies of asymptomatic HIV-infected subjects more than 30 years ago. In contrast to CD8+ T cell cytotoxic lymphocyte (CTL) activity, CNAR suppresses HIV replication without target cell killing. This activity has characteristics of innate immunity: it acts on all retroviruses and thus is neither epitope specific nor HLA restricted. The HIV-associated CNAR does not affect other virus families. It is mediated, at least in part, by a CD8+ T cell antiviral factor (CAF) that blocks HIV transcription. A variety of assays used to measure CNAR/CAF and the effects on other retrovirus infections are described. Notably, CD8+ T cell noncytotoxic antiviral responses have now been observed with other virus families but are mediated by different cytokines. Characterizing the protein structure of CAF has been challenging despite many biologic, immunologic, and molecular studies. It represents a low-abundance protein that may be identified by future next-generation sequencing approaches. Since CNAR/CAF is a natural noncytotoxic activity, it could provide promising strategies for HIV/AIDS therapy, cure, and prevention.

Increased Cortical Cerebral Blood Flow in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Human immunodeficiency virus (HIV)-infected individuals are at high risk for ischemic stroke. To investigate the physiological basis for this risk, we used magnetic resonance imaging (MRI) to measure oxygen extraction fraction (OEF) and cerebral blood flow (CBF) in treatment-naive asymptomatic HIV-infected subjects and controls. In treatment-naive asymptomatic HIV-infected subjects and age-, gender-, and race-matched controls, OEF was measured by MRI asymmetric spin-echo echo-planar imaging sequences and CBF was measured by MRI pseudocontinuous arterial spin labeling. Twenty-six treatment-naive HIV-infected subjects and 27 age-, gender-, race-matched controls participated. Whole-brain, gray matter (GM), and white matter OEF were not different between the groups (all P > .70). Unexpectedly, HIV-infected subjects had significantly higher CBF in cortical GM (72.9 ± 16.2 mL/100 g/min versus 63.9 ± 9.9 mL/100 g/min; P = .01) but not in subcortical GM (P = .25). The observed increase in cortical GM CBF in treatment-naive HIV-infected subjects is unexpected, contrary to CBF decreases reported in HIV-infected subjects on treatment, and may represent an initial increase in metabolic activity due to an HIV-mediated inflammation.

Colorectal Cancer Screening in Asymptomatic HIV-Infected Subjects: High Rates of Mucosal Abnormalities

Colorectal Cancer Screening in Asymptomatic HIV-Infected Subjects: High Rates of Mucosal Abnormalities

Comprehensive Cardiac Magnetic Resonance Imaging and Spectroscopy Reveal a High Burden of Myocardial Disease in HIV Patients

HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.

Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy

BackgroundNeopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression.MethodsCSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naïve or had been off ART for ≥ 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison.ResultsNon-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels.ConclusionsAfter virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation.

Two patterns of cerebral metabolite abnormalities are detected on proton magnetic resonance spectroscopy in HIV-infected subjects commencing antiretroviral therapy

Cerebral function impairment remains problematic in subjects with chronic human immunodeficiency virus (HIV) infection despite effective combination antiretroviral therapy (cART). Using cerebral proton magnetic resonance spectroscopy ((1)H MRS), we aimed to determine if abnormalities could be detected in neurologically asymptomatic HIV-infected subjects electively commencing cART. Therapy-naive, HIV-infected individuals and HIV-uninfected controls underwent (1)H MRS in several anatomical voxels including the mid-frontal grey matter (FGM) and right basal ganglia (RBG). Differences in cerebral metabolite ratios between groups and correlations between immune and virological status were assessed. Forty-six subjects were recruited (26 HIV-infected and 20 control subjects). In the HIV-infected group, mean CD4+ count (SD, cells per microlitre) and plasma HIV RNA (SD, log10 copies per millilitre) were 192 (86) and 4.71 (0.64), respectively. Choline (Cho)/Creatine (Cr) and myoinositol (MI)/Cr ratios were significantly lower in the FGM in HIV-infected subjects compared to controls (0.67 (0.14) versus 0.88 (0.49), p = 0.036, and 0.94 (0.28) and 1.17 (0.26), p = 0.008, for Cho/Cr and MI/Cr, respectively) and Cho/Cr ratio associated with CD4+ lymphocyte count (p = 0.041). N-Acetyl-aspartate (NAA)/Cho ratio was significantly lower in the RBG in HIV-infected subjects compared to controls (2.27 (0.54) versus 2.63 (0.68), p = 0.002), and this was associated with greater plasma HIV RNA load (p = 0.014). Two patterns of cerebral metabolite abnormalities were observed in HIV-infected subjects electively commencing cART. Greater inflammatory metabolite ratios (Cho/Cr and MI/Cr) associated with lower markers of peripheral immune markers (CD4+ lymphocyte count) in the FGM and lower neuronal metabolite ratios (NAA/Cho) associated with greater HIV viraemia in the RBG were present in HIV-infected subjects.

Serum Retinol-Binding Protein-4 Levels Are Increased in HIV-Infected Subjects with Metabolic Syndrome Receiving Highly Active Antiretroviral Therapy

Metabolic syndrome is an important long term complication in chronic asymptomatic HIV-infected subjects under highly active antiretroviral therapy (HAART), because it can contribute to morbidity and mortality via cardiovascular disease (CVD). Therefore, a predictive marker for early detection of metabolic syndrome may be necessary to prevent CVD in HIV-infected subjects. Retinol-binding protein-4 (RBP-4) has been shown to be associated with metabolic syndrome in various non-HIV-infected populations. We performed a cross-sectional study to evaluate whether serum RBP-4 levels are correlated with metabolic syndrome in HIV-infected subjects receiving HAART. In total, 98 HIV-infected Koreans who had been receiving HAART for at least 6 months were prospectively enrolled. Metabolic syndrome was diagnosed according to the Adult Treatment Panel III criteria, and serum RBP-4 concentrations were measured using human RBP-4 sandwich enzyme-linked immunosorbent assay. Serum RBP-4 levels were significantly higher in HIV-infected subjects receiving HAART with metabolic syndrome (n=33, 33.9±7.7 µg/mL) than in those without it (n=65, 29.9±7.2 µg/mL) (p=0.012). In multivariate linear regression analysis, the number of components of metabolic syndrome presented and waist circumference were independently, significantly correlated with RBP-4 (p=0.018 and 0.030, respectively). In conclusion, we revealed a strong correlation between RBP-4 and the number of components of metabolic syndrome in HIV-infected subjects receiving HAART.

Significant coronary stenosis detected by coronary computed angiography in asymptomatic HIV infected subjects

increased incidence of acute coronary events, high rate of abnormal surrogate markers of atherosclerosis and increased amount of coronary calcium have been described in HIV infected population. To expand knowledge on coronary artery disease (CAD) in HIV patients, cardiac CT scan was performed in asymptomatic subjects with low cardiovascular (CV) risk. A cross-sectional study using dual-source CT (MDCT) coronary angiography.was conducted in HIV-infected subjects with the following characteristics: Framingham Risk Score (FRS) ≤10, absence of metabolic syndrome, negative echocardiographic and ECG stress-test. A luminal narrowing exceeding 50% was defined as a clinically significant coronary stenosis. Calcium score was quantified using the Agatston Calcium Score method. Fifty-five subjects were enrolled. Significant coronary stenoses, requiring coronary angiography, were found in 16/55 (29.1%). At multivariate analysis older age was the only variable independently associated with the presence of significant luminal narrowing (p=0.011). MDCT showed an unexpected, age-associated high rate of significant coronary stenosis in asymptomatic HIV positive subjects with low CV risk. These findings suggest that aggressive screening programs for coronary artery disease may be appropriate in this population; further studies are recommended to assess the appropriateness of MDCT for this purpose.

Screening colonoscopy for the detection of neoplastic lesions in asymptomatic HIV-infected subjects

Background:Although non-AIDS defining malignancies are rapidly increasing as HIV-infected subjects live longer, little is know about the results of screening for colonic neoplasms (adenomatous polyps and adenocarcinomas) in this population.Methods:We...

Both IgA subclasses are reduced in parotid saliva from patients with AIDS

Secretory IgA (SIgA), the isotypes IgA1 and IgA2, and IgM were measured by ELISA in stimulated parotid saliva from patients with AIDS (n = 16), subjects with asymptomatic HIV infection (n = 28), and HIV-seronegative healthy controls (n = 19). SIgA was significantly reduced in the AIDS group (10.4 micrograms/ml) compared with the asymptomatic HIV-infected subjects (17.1 micrograms/ml) and the controls (23.0 micrograms/ml). This decrease comprised both IgA1 and IgA2 to a similar extent on a relative basis. The SIgA decrease in AIDS patients was in striking contrast to their serum IgA level, which was significantly increased (6.9 g/l) compared with the asymptomatic HIV-infected subjects (2.9 g/l) as well as the controls (2.8 g/l). Low parotid output of SIgA in patients with HIV infection was associated with low numbers of CD4+ lymphocytes in peripheral blood as well as the presence of oral infections. The parotid output of IgM was similar in all groups. A low level of SIgA in the external secretions of patients with AIDS may well contribute to their frequent mucosal infections of opportunistic microorganisms.

A population pharmacokinetic meta‐analysis of maraviroc in healthy volunteers and asymptomatic HIV‐infected subjects

To develop a population pharmacokinetic model for maraviroc, a noncompetitive CCR5 antagonist, after oral administration of tablets to healthy volunteers and asymptomatic HIV-infected subjects and to quantify the inherent variability and influence of covariates on the parameters of the model. Rich pharmacokinetic data available from 15 studies in healthy volunteers (n = 365) and two studies in asymptomatic HIV-infected subjects (n = 48) were analysed using NONMEM. Maraviroc was administered as single or multiple oral tablet doses under fasted and fed conditions. Doses ranged from 100 to 1800 mg day(-1). A two-compartment model parameterized to separate out absorption and clearance components on bioavailability was used. Absorption was described by a lagged first-order process. A sigmoid E(max) model described the effect of dose on absorption. A visual predictive check and nonparametric bootstrap evaluation confirmed that the model was a good description of the data. Typical CL, V(c) and V(p) values for a 30-year-old non-Asian are 51.5 l h(-1), 132 l and 277 l, respectively. For the typical non-Asian subject, fasted bioavailability increased asymptotically with dose from 24% at 100 mg to 33% at 600 mg. A high-fat meal taken with maraviroc reduced exposure by 43% for a 100-mg dose to approximately 25% at doses of 600 mg. The typical Asian subject had a 26.5% higher AUC than the typical non-Asian subject irrespective of dose, a difference not considered to be clinically relevant. None of the other covariates tested had any clinically relevant effects on exposure.

Quality of life in HIV subtype C infection among asymptomatic subjects and its association with CD4 counts and viral loads – a study from South India

To study the association between quality of life (QOL) domains and biological markers of disease progression of HIV infection, i.e. viral load (VL) and CD4 counts among asymptomatic subjects with HIV subtype C infection in South India. Quality of life was measured using the locally validated version of the WHOQOL HIV-BREF. The subjects were neurologically asymptomatic, non psychiatrically ill HIV infected men and women participating in a cohort study. The results indicated mixed findings, with some QOL dimensions being associated with high VLs and low CD4 counts while several others did not show any associations. Significant associations were seen between low CD4 counts and the psychological and social relationships domain, with lower mean scores in these domains being reported by subjects having CD4 counts <200/mm. However, there were no significant differences between the CD4 subgroups for the domains related to physical health, level of independence, environment, and spirituality domains. Significant lower mean QOL scores were found in the highest VL subgroup compared to other groups for the following WHOQOL HIV-BREF domains: physical, psychological, level of independence, and environmental. In this sample of HAART naïve asymptomatic HIV infected subjects, some QOL dimensions were associated with the biological markers of disease progression i.e. VL and CD4 counts, while several were not. The associations were significant only in the high VL and low CD4 groups.

Pneumocystis Colonization, Airway Inflammation, and Pulmonary Function Decline in Acquired Immunodeficiency Syndrome

As a result of improved diagnosis, treatment, and supportive care for HIV-infected patients, AIDS in developed countries has now become a chronic infection with prolonged survival time, but longterm complications are increasing contributors to morbidity and mortality. HIV-infected patients are at increased risk for the development of pulmonary complications, including chronic obstructive pulmonary disease (COPD); however, the mechanisms associated with this increased susceptibility have not been defined. Infectious agents may contribute to the development of COPD by upregulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to asymptomatic carriage or colonization by the opportunistic pathogen, Pneumocystis sp. (Pc), is similar to that of COPD, which is characterized by influx of CD8+ T cells, neutrophils, and macrophages into the lungs. We have shown a high frequency of Pc colonization among asymptomatic HIV-infected subjects and in non-HIV infected subjects with COPD. To investigate the role of Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc colonizatoin and infection in simian immunodeficiency virus (SIV)-infected macaques. These animals develop a prolonged colonization state characterized by a persistent influx of CD8+ T cells and neutrophils, and local increases in IL-8, IFN-gamma, and TNF-alpha. SIV-infected Pc-colonized monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. Information gained from these studies will lead to the development of interventions to prevent lung injury associated with Pc colonization and the development of HIV-associated COPD.

The nutritional status of asymptomatic HIV-infected Africans: directions for dietary intervention?

To compare the relationships between food (nutrient) intakes and biochemical markers of nutritional status of asymptomatic HIV-infected with HIV-uninfected subjects, to gain more information on the appropriate diet for HIV-infected persons at an early stage of infection. Cross-sectional population-based survey. North West Province, South Africa. Two hundred and sixteen asymptomatic HIV-infected and 1550 HIV-uninfected men and women volunteers aged 15 years and older, recruited as 'apparently healthy' subjects from 37 randomly selected sites. Food and nutrient intakes, measured with a validated food-frequency questionnaire, and nutritional status indicated by anthropometric and biochemical variables, measured by a standardised methodology. The prevalence of HIV infection in the study population was 11.9%. The anthropometric indices and nutrient intakes of HIV-infected and uninfected subjects did not differ significantly, indicating that these 216 HIV-infected subjects were at an early stage of infection. Of the biochemical nutritional status variables, high-density lipoprotein cholesterol and total cholesterol, haemoglobin, albumin and triglycerides were significantly lower in infected subjects. They also had higher globulin and liver enzyme levels than uninfected subjects. In infected subjects, serum albumin correlated significantly with serum lipids, serum vitamin A, serum vitamin E, serum iron, total iron-binding capacity and haemoglobin. The significant positive correlations of the liver enzymes with serum lipids, albumin, vitamin A and iron, observed in HIV-uninfected subjects, disappeared in the infected subjects. Polyunsaturated fat intake showed significant positive correlations with the increased liver enzymes in infected subjects. A principal components analysis indicated that, in infected subjects, increased liver enzymes correlated with higher consumption of maize meal and lower consumption of meat and vegetables. This survey indicated that asymptomatic HIV-infected subjects who followed a diet rich in animal foods had smaller decreases in serum albumin, haemoglobin and lipid variables, and smaller increases in liver enzymes, than those who consumed a diet based on staple foods. This suggests that animal foods are associated with improved nutritional status in HIV-infected persons. These results should be confirmed with intervention studies before dietary recommendations for asymptomatic HIV-infected individuals can be made.

Therapeutic immunization with an inactivated HIV-1 Immunogen plus antiretrovirals versus antiretroviral therapy alone in asymptomatic HIV-infected subjects

To determine whether the addition of an inactivated-gp120-depleted HIV-1 Immunogen to antiretrovirals (ARTs) conferred a beneficial effect on delaying time to virologic failure relative to that obtained by ARTs alone, a phase II clinical trial was performed in 243 asymptomatic, ART naı̈ve, HIV-1 seropositive adults. The Cox model showed that HIV-1 Immunogen treatment was associated with a 34% decrease in the risk of virologic failure ( P=0.056). When the analysis incorporated baseline HIV-RNA stratification the risk of virologic failure in the HIV-1 Immunogen Arm was significantly reduced a 37% compared to the IFA placebo Arm ( P=0.034). The data suggest that therapeutic immunization plus ARTs could influence virologic control.

Effect of protease therapy on cytokine secretion by peripheral blood mononuclear cells (PBMC) from HIV-infected subjects.

The viral load reduction seen in patients with late stage HIV infection treated with the protease inhibitor, ritonavir, is accompanied by increases in the in vitro proliferative responses generated by PBMC. The present study was undertaken to investigate which lymphocyte subsets generated these responses and the effects of therapy on cytokine production. Lymphoproliferation following phytohaemagglutinin (PHA) stimulation was studied by thymidine incorporation, and production of IL-2, interferon-gamma (IFN-gamma) and IL-4 was assessed by ELISA in 12 patients receiving ritonavir and seven receiving placebo in the context of randomized, blinded clinical trials. CD4+ cell-depleted and CD8+ cell-depleted subsets were obtained from PBMC by immunomagnetic bead depletion. At week 4 of therapy a two-fold or greater increase in proliferative responses was observed in 9/12 subjects receiving therapy, compared with 0/7 receiving placebo. Similarly there was a significant increase in IL-2 and IFN-gamma production of 2.7-fold (P = 0.02) and 1.7-fold (P = 0.03), respectively, in the treatment group compared with those receiving placebo. No change in IL-4 production was observed. Despite these increases, cytokine responses post-therapy were still reduced compared with both healthy controls and asymptomatic HIV-infected subjects. Increases in proliferative response and IL-2 production were greater in the CD8+ cell-depleted population than in the CD4+ cell-depleted population, whereas increases in IFN-gamma production were derived from the CD4+ cell-depleted population.

Sensory evoked potentials in SIV-infected monkeys with rapidly and slowly progressing disease.

Human immunodeficiency virus (HIV-1) infects the central nervous system (CNS) early in the course of disease progression and leads to some form of neurological disease in 40-60% of cases. Both symptomatic and asymptomatic HIV-infected subjects also show abnormalities in evoked potentials. As part of an effort to further validate an animal model of the neurological disease associated with lentiviral infection, we recorded multimodal sensory evoked potentials (EPs) from nine rhesus macaques infected with passaged strains of SIVmac (R71/E17), prior to and at 1 month intervals following inoculation. The latencies of forelimb and hindlimb somatosensory evoked potentials (SEP) and flash visual evoked potentials (VEP) were measured. Within 14 weeks of inoculation, all but two animals had progressed to end-stage disease (rapid progressors). The two animals with slowly progressing disease (AQ15 and AQ94) had postinoculation life spans of 109 and 87 weeks, respectively. No significant changes were observed in evoked potentials recorded during the control period or at any time in the animals with slowly progressing disease. However, all of the monkeys with rapidly progressing disease exhibited increases in latency for at least one evoked potential type. The overall mean increases in somatosensory and visual evoked potential peak latencies for the rapid progressors were 22.4 and 25.3%, respectively. For comparison, the changes in slow progressors were not significant (1.8 and -1.9%, respectively). These results, coupled with our previous finding of slowed motor evoked potentials in the same cohort of macaques (Raymond et al.: J Neurovirol 1999;5:217-231), demonstrate a broad and somewhat variable pattern of viral injury to both sensory and motor system structures, resembling the findings in HIV-infected humans. These results coupled with our earlier work demonstrating cognitive and motor behavioral impairments in the same monkeys support the use of the SIVmac-infected rhesus macaque as a model of AIDS-related neurological disease.

Changes in condom use after HIV diagnosis.

We investigated changes in condom use after HIV diagnosis. The study population comprised 78 asymptomatic HIV-infected subjects recruited from a clinic in Oslo, Norway, during 1988-92. In total, 240 follow-up visits were carried out. The response variable was repeated measurements of whether or not condoms were always used during anal/vaginal intercourse at follow-up. The explanatory variables were: time from HIV diagnosis to follow-up, exposure group (heterosexually infected, homosexual men, or infected through injecting drug use), time of HIV diagnosis (before 1987 or later), and history of condom use before HIV diagnosis. Random effects logistic regression analysis was used to study incremental changes in condom use, accommodating an unbalanced repeated measurement design. The use of condoms increased monotonously over time after HIV diagnosis in all exposure groups. Condom use was least likely among injecting drug users, subjects diagnosed before 1987 and subjects without a history of frequent condom use before HIV diagnosis.

Large clonal expansions of human virus‐specific memory cytotoxic T lymphocytes within the CD57+ CD28– CD8+ T‐cell population

The proportion of human peripheral blood CD8+ T cells that are CD57+ CD28- is low at birth but increases with age and in individuals infected with human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV). These CD57+ CD28- CD8+ T cells contain large oligoclonal T-cell expansions whose antigen specificity is unknown. We identified clonal expansions of virus-specific memory cytotoxic T-lymphocyte precursors (CTLp) in both healthy carriers of HCMV and in asymptomatic HIV-infected subjects. In each subject, from the T-cell receptor (TCR) beta-chain hypervariable sequence of each immunodominant CTL clone, we designed complementary oligonucleotide probes to quantify the size and phenotypic segregation of individual virus-specific CTL clones in highly purified populations of peripheral blood CD8+ T cells. We found large clonal expansions of virus-specific CTL clonotypes in CD57+ CD28- CD8+ T cells. Using limiting dilution analysis, we found functional peptide-specific CTLp at high frequency in CD57+ CD28- cells. Thus, memory CTL specific for persistent viruses account for many oligoclonal expansions within CD57+ CD28- CD8+ T cells.

Lymphocytic Alveolitis, Bronchoalveolar Lavage Viral Load, and Outcome in Human Immunodeficiency Virus Infection

Lymphocytic alveolitis portends a poor prognosis in human immunodeficiency virus (HIV)-infected subjects. Because alveolar lymphocytes consist predominantly of HIV-specific CD8(+) cytotoxic T lymphocytes (CTL), they could represent an appropriate immune response to infected cells in the lung, and be a surrogate marker for a high pulmonary viral burden. We assessed long-term outcome in a cohort of asymptomatic HIV-infected subjects who underwent bronchoscopy between 1990 and 1993 and had bronchoalveolar lavage fluid (BALF) available for determination of viral load by reverse transcription-polymerase chain reaction. The ability to detect HIV in BALF increased with disease progression. Lymphocytic alveolitis, although present at all stages of HIV infection, was most pronounced in patients with middle stage disease. The HIV viral load as measured by bronchoalveolar lavage correlated with the percentage of alveolar lymphocytes in patients with peripheral blood CD4(+) cell counts above 200/microliter. Including patients with CD4(+) cell counts < 200/microliter weakened this correlation, possibly because of replacement of CD8(+) CTL by CD8(+) suppressor cells in advanced disease. Free virus in BALF was a stronger predictor of HIV disease progression than was lymphocytic alveolitis. These data suggest that lymphocytic alveolitis in HIV-infected subjects occurs in response to viral antigens in the lung and that the poor prognosis associated with lymphocytic alveolitis reflects a high pulmonary viral burden.