Late-stage HIV Infection Research Articles

Th1/Th2 shift in HIV lymph nodes: no contribution of CD6o cells.

An expansion of CD8+60+ cells with Th2 type helper function has been observed in HIV-infected individuals. A Th1/Th2 shift in late HIV infection might be related to the functional activity of this subset. Our objective was to test the ability of lymph node (LN) lymphocytes to produce cytokines of the Th1 and Th2 type. LN cells were stimulated with PMA in the presence of ionomycin and brefeldin A. After surface staining for CD4, CD8 and CD60 and intracellular staining for interferon gamma (IFNgamma), interleukin 2 (IL-2) or IL-4 and IL-10, the percentage of cytokine producing lymphocytes (CPL) was determined by flow cytometry. LN of nine individuals in the early stage of HIV infection were compared to late stage patients. CD4+ subset: in early stages of HIV infection the percentage of Th1 CPL was 1.9 times higher than that of Th2 CPL. In late stages of infection the Th1 responding cells were not found more frequently than Th2 ceLLs. CD8+ subset: no Th1/Th2 shift was detected during early or late stages of HIV infection. CD60+ subset: a maximum of 32.1 +/- 7.8% of double positive cells of the CD8+60+ type produced Th2 type cytokines. A small percentage (< 8%) of CD60+ cells also produced Th1 cytokines. No shift in the cytokine production was seen in early or late stages of infection. At single cell level a shift in cytokine production in LN cells can only be detected in the CD4+ subset. Thus, the CD60+ subset does not seem to contribute to the putative Th1/Th2 shift attributed to the immunopathogenesis of HIV-induced destruction of the immune system.

New-onset seizures associated with HIV infection.

The authors studied new-onset seizures in 60 heterosexual black South African HIV-infected patients who had not used IV drugs. An intracranial space-occupying lesion was identified in 53% of patients, meningitis in 22%, and no additional cause in 25%. Of the patients with an identifiable cause, 64% had probable tuberculosis (tuberculoma or tuberculous meningitis). The majority of patients had late-stage HIV infection (CD4 counts <200/mm(3)).

Chemokine receptors in HIV-1 and SIV infection.

Seven transmembrane segment (7TMS) receptors for chemokines and related molecules have been demonstrated to be essential, in addition to CD4, for HIV and SIV infection. The beta-chemokine receptor CCR5 is the primary, perhaps sole, coreceptor for HIV-1 during the early and chronic phases of infection, and supports infection by most primary HIV-1 and many SIV isolates. Late-stage primary and laboratory-adapted HIV-1, HIV-2, and SIV isolates can use other 7TMS receptors. CXCR4 appears especially important in late-stage HIV infection; several related receptors can also be used. The specificity of SIV viruses is similar. Commonalities among these receptors, combined with analyses of mutated molecules, indicate that discrete, conformationally-dependent sites on the chemokine receptors determine their association with the third variable and conserved regions of viral envelope glycoproteins. These studies are useful for elucidating the mechanism and molecular determinants of HIV-1 entry, and of inhibitors to that entry.

Identification of inflections in T-cell counts among HIV-1-infected individuals and relationship with progression to clinical AIDS.

Studies of circulating T (CD3(+)) lymphocytes have shown that on a population basis T-cell numbers remain stable for many years after HIV-1 infection (blind T-cell homeostasis), but decline rapidly beginning approximately 1.5-2.5 years before the onset of clinical AIDS. We derived a general method for defining the loss of homeostasis on the individual level and for determining the prevalence of homeostasis loss according to HIV status and the occurrence of AIDS in more than 5,000 men enrolled in the Multicenter AIDS Cohort Study. We used a segmented regression model for log10 CD3(+) cell counts that included separate T-cell trajectories before and after a time (the T-cell inflection point) where the loss of T-cell homeostasis was most likely to have occurred. The average slope of CD3(+) lymphocyte counts before the inflection point was close to zero for HIV- and HIV+ men, consistent with blind T-cell homeostasis. After the inflection point, the HIV+ individuals who developed AIDS generally showed a dramatic decline in CD3(+) cell counts relative to HIV- men and HIV+ men not developing AIDS. A CD3(+) cell decline of greater than 10 percent per year was present in 77% of HIV+ men developing AIDS but in only 23% of HIV+ men with no onset of AIDS. Our findings at the individual level support the blind T-cell homeostasis hypothesis and provide strong evidence that the loss of homeostasis is an important mechanism in the pathogenesis of the severe immunodeficiency that characterizes the late stages of HIV infection.

Kaposi's sarcoma in HIV infection: impact on opportunistic infections and survival.

To determine the effect of Kaposi's sarcoma on survival of HIV-infected patients. Retrospective cohort study to compare the survival of 241 HIV-infected homosexual patients with Kaposi's sarcoma (cases) with that of 241 HIV-infected homosexual patients without Kaposi's sarcoma (control subjects) but with a similar level of immunosuppression (measured by the absolute CD4+ lymphocyte count). Cases and control subjects were similar in age, occurrence of previous opportunistic infections, and the use of antiretroviral therapy. The mean CD4+ lymphocyte counts were similar for cases and control subjects (185 x 10(6) versus 184 x 10(6)/l, respectively). Cases had a higher incidence of opportunistic infections (5.95 versus 3.88 infections, respectively, per 100 person-months of observation) and a greater number of infections typical of late-stage HIV infection. Cases had a shorter overall survival than did control subjects (P=0.0025). Kaposi's sarcoma was associated with an increased risk of death (odds ratio, 1.28), even when adjusting for age, previous opportunistic infection, baseline CD4+ lymphocyte count, and antiretroviral therapy. Kaposi's sarcoma appears to accelerate the clinical course of HIV infection. Opportunistic infections develop earlier and more often in patients with the disease than in control subjects. Survival was significantly shorter in patients with Kaposi's sarcoma.

Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS

Certain aspects of the clinical syndrome of dementia, cerebral atrophy, predominantly sensory neuropathy, and vacuolar myelopathy in AIDS resemble those seen in vitamin B12 deficiency. Pathologically, there are similarities not...

Improving HIV Therapy

HIV PROVIRUS Avaccine would certainly be ideal for preventing infection by HIV and thus for avoiding AIDS—the late stage of HIV infection, when immunity is severely impaired. Yet the near-term prospects for a vaccine are poor, and people who contract the virus need care. For the immediate future, then, many scientists are concentrating on improving therapy. Until only a few years ago, HIV infection was everyone’s worst nightmare— it was almost invariably a progressive, lethal disease that completely robbed its victims of dignity. Most medical interventions focused on treating pneumonias and other serious “opportunistic” infections that stemmed from immune failure, not on controlling HIV itself. Since late 1995, however, several related advances have led to a profound shift in the prospects for most patients who receive treatment today. Notably, scientists have gained a much fuller understanding of how HIV behaves in the body and a better sense of how to shackle it. Two classes of potent drugs have joined the anti-HIV arsenal, and tests that can directly monitor viral levels have been introduced, enabling physicians to assess a therapy’s effectiveness rapidly. Together these advances have made it possible to treat HIV infection aggressively and to improve health and survival—at least in the industrial nations, where the intensive therapy is now widely available. Initially, the signs of a sea change were anecdotal: extraordinary but increasingly frequent tales of people who were plucked from the brink of death to resume vigorous, productive lives. More recently, statistics have borne out the anecdotes. Between the first half of 1996 and the first half of 1997, deaths from AIDS in the U.S. declined by 44 percent. In roughly the same period the frequency of HIV-related hospitalizations and major HIV complications dropped markedly as well. Nevertheless, both scientific understanding and treatment remain far from perfect. For instance, researchers do not know whether the impressive responses to therapy can be sustained. Treatment Improving HIV Therapy

Structural interactions between chemokine receptors, gp120 Env and CD4

Seven transmembrane segment (7TMS) receptors for chemokines and related molecules have been demonstrated to be essential, in addition to CD4, for HIV and SIV infection. The β-chemokine receptor CCR5 is the primary, perhaps sole, co-receptor for HIV-1 during the early and chronic phases of infection and supports infection by most primary HIV-1 and many SIV isolates. Late-stage primary and laboratory-adapted HIV-1, HIV-2, and SIV isolates can use other 7TMS receptors. CXCR4 appears especially important in late-stage HIV infection; several related receptors can also be used. The specificity of SIV viruses is similar. Commonalities among these receptors, combined with analyses of mutated molecules, indicate that discrete, conformationally-dependent sites on the chemokine receptors determine their association with the third variable and conserved regions of viral envelope glycoproteins. These studies are useful for elucidating the mechanism and molecular determinants of HIV-1 entry, and of inhibitors to that entry.

No evidence for proliferation in the blood CD4+ T-cell pool during HIV-1 infection and triple combination therapy.

To evaluate the role of cell proliferation in peripheral blood lymphocyte (PBL) dynamics during HIV infection and potent antiretroviral therapy including protease inhibitors. Transverse study of 150 patients at different stages of infection. Longitudinal study of 50 patients on triple combination antiretroviral therapy with 9-month follow-up. Ex vivo incubation of fresh PBL with the DNA biosynthetic marker bromodeoxyuridine (BrdU). Flow cytometric analysis of cell phenotypes and BrdU incorporation. Parallel determination of plasma virus load and CD4+ cell counts. Percentages of BrdU+ B and T lymphocytes found in patients with asymptomatic HIV infection were not different from the low values found in HIV-seronegative controls, and were not correlated with the CD4+ cell count. DNA synthesis increased significantly only during acute opportunistic infections occurring in patients with high plasma viral load and fewer than 100 x 10(6) CD4+ cells/l. Triple combination therapy induced a decrease of plasma virus load and a rise of CD4+ cell counts, whereas BrdU incorporation remained low or decreased. Proliferation of peripheral blood T cells observed at late stages of HIV infection corresponds to a response to opportunistic infections. Apart from these particular cases, proliferation in this compartment does not appear as a critical parameter of CD4+ cell kinetics during chronic HIV infection and potent therapy.

Congenital and perinatal cytomegalovirus infection in infants born to mothers infected with human immunodeficiency virus

Objectives: To determine the rates of congenital and perinatal cytomegalovirus (CMV) infection among infants born to mothers infected with HIV compared with infants born to mothers not infected with HIV from a CMV-immune, low-income population. Study design: A total of 325 newborns from CMV-seropositive mothers were enrolled and evaluated for congenital CMV infection (150 infants from HIV + mothers and 175 infants from HIV - mothers. A total of 101 infants from HIV + mothers and 33 infants from HIV - mothers were evaluated for perinatal CMV infection. The virus was isolated from urine by culture in human fibroblasts and was detected by polymerase chain reaction at birth and at 15 days and 12 weeks of age. Results: Only 13 of 150 HIV + mothers (8.7%) had an AIDS-defining condition, and none had a late-stage HIV infection. Congenital CMV infection was detected in 4 of 150 (2.7%) infants from HIV + mothers and in 5 of 175 (2.9%) infants from HIV - mothers ( p = 1.00). Perinatal CMV infection was diagnosed in 8 of 101 (7.9%) infants from HIV + mothers and in 13 of 33 (39.4%) infants from HIV - mothers ( p < 0.00001). Most infants (93.9%) from HIV - mothers and only 5.9% of infants from HIV + mothers were breastfed. Conclusions: CMV coinfection in mothers without advanced HIV disease from a CMV-immune population does not enhance the likelihood of congenital CMV infection. Perinatal CMV transmission from HIV-infected mothers may be decreased by avoiding breastfeeding. Further studies on mothers with late-stage HIV infection are needed. (J Pediatr 1998;132:285-90)

Mood disorders in HIV infection.

Summary Major depression and mania have increased prevalence in HIV-infected patients, particularb in clinical settings and at later stages of disease. Varied rates of major depression have been reported but dzzerences in definition, methods of study, and population may partly explain these dafferences. We describe the clinical characteristics, assessment and treatment of mood disorders in HIV-infected patients, with emphasis on aspects specific to the setting of HIV infection. Diagnosis and treatment are complicated by medical complexity, stigma and psychosocial stress. Treatment is associated with clinical improvement. Mood disorders are associated with impulsivity, substance abuse, hopelessness, and demoralization, all of which may increase risk for HIV infection. Also, HIV-associated subcortical damage may be a risk factor for mood disorders, which are increased in late stage HIV infection. We discuss the data supporting the thesis that both of these factors may be at work in producing the high rates of mood disorders seen, and speculate that aggressive treatment of mood disorders may improve outcome and risk behaviors in HIV-infected patients.

Characteristics of IgA anti-HIV antibodies in plasma from patients with HIV infection.

The concentration of total IgA and the specificity and molecular size of IgA anti-human immunodeficiency virus (HIV) type-1 antibodies in plasma obtained from individuals at different stages of HIV infection were analyzed. The concentration of total IgA in the plasma was not decreased even in the late stage of HIV infection, in contrast with those of total IgG and IgM. The IgA anti-HIV antibodies differed to the IgG anti-HIV antibodies in their specificity as determined by Western blotting. The IgA antibodies mainly bind to Env glycoproteins. The IgA anti-HIV antibodies in plasma were detected between IgG and IgM by gel filtration, suggesting the presence of polymeric IgA anti-HIV antibodies. These results indicate that the production of non-specific IgA in plasma is enhanced by unknown mechanisms in every stages of HIV infection, and suggest that IgA anti-HIV antibodies in plasma which are possibly polymeric and have unique specificity may play an important role in HIV infection.

Increased losses of CD4+CD45RA+ cells in late stages of HIV infection is related to increased risk of death: evidence from a cohort of 347 HIV-infected individuals.

To examine changes in the distribution of CD4+CD45RA+ (naive) and CD4+CD45RO+ (memory) lymphocytes in various stages of HIV infection and the effect of these changes on disease progression. Expression of CD45RA+ and CD45RO+ on CD4+ lymphocytes was analysed by flow cytometry in a prospectively followed cohort of 300 HIV-infected individuals (median follow-up time, 2.90 years; range, 0.02-4.54 years) and in a group of 102 age- and sex-matched uninfected controls. Survival analysis was performed considering AIDS development and death as endpoints. The median CD4+CD45RA+/CD45RO+ ratio was 1.3 (25-75% quartiles, 0.9-2.4) in controls; it was increased to 1.8 (1.1-2.5) in 40 HIV-infected individuals with CD4+ cell counts > 500 x 10(6)/l (P < 0.05); it was similar at 1.4 (0.8-2.0) in 106 HIV-infected individuals with CD4+ cell counts of 200-500 x 10(6)/l; and it was decreased to 0.9 (0.5-1.4) in 154 HIV-infected individuals with CD4+ cell counts < 200 x 10(6)/l (P < 10[-6]). When fitted in a Cox model adjusting for the total number of CD4+ cells and age a lower concentration of CD4+CD45RA+ cells was associated with an increased risk of dying. The concentration of CD4+CD45RO+ cells was not significantly associated with AIDS or death in age- and CD4+ cell count-adjusted Cox models. This study confirms a selective loss of memory CD4+ cells early in HIV infection followed by increased loss of naive CD4+ cells in later stages of the infection. The loss of naive CD4+ cells seems to be important in the pathogenesis of terminal HIV infection.

Temporary seronegativity in a human immunodeficiency virus type 1-infected man

Over a period of 3 months a human immunodeficiency virus 1 (HIV-1)-infected patient showed a sequence of positive-negative-positive anti-HIV screening test results. During this period the level of HIV p24 antigen declined and the HIV antibody pattern by Western blot gradually became complete, suggesting recent HIV infection. However the patient's weight loss, esophageal candidiasis, and Pneumocystis carinii pneumonia, together with the severely and persistently lowered CD4 cell counts and the absence of an IgM anti-HIV response, suggest late-stage HIV infection. Despite additional and follow-up testing, it was impossible to determine whether the patient suffered from acute, primary HIV infection with severe immunodepression or from advanced HIV infection (AIDS) with hampered HIV antibody production leading to false-negative test results by the anti-HIV enzyme immunoassay and Western blot. This case illustrates that HIV serology does not always follow the rules. The presence of HIV infection should be considered in a patient showing clinical signs of acute or late-stage HIV infection, even if the anti-HIV assay is negative.

Survival From Early, Intermediate, and Late Stages of HIV Infection

<h3>Objective.</h3> —To estimate expected survival time among homosexual men infected with the human immunodeficiency virus type 1 (HIV-1) by (1) the calendar period before (1985-1988) and after (1989-1993) the widespread availability of acquired immunodeficiency syndrome (AIDS) treatments with antiretroviral and prophylactic interventions, and (2) stage of HIV disease. <h3>Design.</h3> —A prospective cohort study. A group of HIV-1—infected homosexual men were followed from July 1985 through June 1993 and evaluated every 6 months for the presence of clinical symptoms and measurement of the CD4 cell count. To measure the effectiveness of AIDS therapies in this nonrandomized study, we used 2 calendar periods as proxy measures of relative intensity of exposure to antiretroviral therapy. Stage of infection was defined by CD4 cell count and presence of HIV-related clinical symptoms or AIDS. <h3>Setting and Study Participants.</h3> —Homosexual men infected with HIV-1 from the Multicenter AIDS Cohort Study. <h3>Main Outcome Measure.</h3> —Survival time based on stage of HIV infection. <h3>Results.</h3> —The percentage of HIV-1—infected individuals free of AIDS and clinical symptoms at baseline who survived 2.5 years according to baseline CD4 cell counts of 0 to 0.100, 0.101 to 0.200, and 0.201 to 0.350× 10⁹/L was 22%, 53%, and 83%, respectively, for the 1985-1988 calendar period, compared with 54%, 71%, and 91%, respectively, for men in the 1989-1993 calendar period. Among men free of AIDS with CD4 cell counts of greater than 0.350× 10⁹/L, the relative hazard of mortality was 1.6 to 2.3 times higher for those with clinical symptoms compared with those free of clinical symptoms. <h3>Conclusions.</h3> —Survival of AIDS-free HIV-1—infected individuals with CD4 cell counts of less than 0.350× 10⁹/L has improved since antiretroviral and HIV prophylactic treatments have become available, but the long-term prognosis remains poor. (<i>JAMA</i>. 1996;275:1329-1334)

Survival from early, intermediate, and late stages of HIV infection

To estimate expected survival time among homosexual men infected with the human immunodeficiency virus type 1 (HIV-1) by (1) the calendar period before (1985-1988) and after (1989-1993) the widespread availability of acquired immunodeficiency syndrome (AIDS) treatments with antiretroviral and prophylactic interventions, and (2) stage of HIV disease. A prospective cohort study. A group of HIV-1-infected homosexual men were followed from July 1985 through June 1993 and evaluated every 6 months for the presence of clinical symptoms and measurement of the CD4 cell count. To measure the effectiveness of AIDS therapies in this nonrandomized study, we used 2 calendar periods as proxy measures of relative intensity of exposure to antiretroviral therapy. Stage of infection was defined by CD4 cell count and presence of HIV-related clinical symptoms or AIDS. Homosexual men infected with HIV-1 from the Multicenter AIDS Cohort Study. Survival time based on stage of HIV infection. The percentage of HIV-1-infected individuals free of AIDS and clinical symptoms at baseline who survived 2.5 years according to baseline CD4 cell counts of 0 to 0.100, 0.101 to 0.200, and 0.201 to 0.350 x 10(9)/L was 22%, 53%, and 83%, respectively, for the 1985-1988 calendar period, compared with 54%, 71%, and 91%, respectively, for men in the 1989-1993 calendar period. Among men free of AIDS with CD4 cell counts of greater than 0.350 x 10(9)/L, the relative hazard of mortality was 1.6 to 2.3 times higher for those with clinical symptoms compared with those free of clinical symptoms. Survival of AIDS-free HIV-1-infected individuals with CD4 cell counts of less than 0.350 x 10(9)/L has improved since antiretroviral and HIV prophylactic treatments have become available, but the long-term prognosis remains poor.

Cardiomyopathy and other symptomatic heart diseases associated with HIV infection.

Approximately 14 million persons worldwide are estimated to be infected with HIV-1. As more effective therapies have produced longer survival times for HIV-infected patients, new complications of late-stage HIV infection including HIV-related heart disease have emerged. The most common and life-threatening cardiovascular complication of HIV infection is the development of primary heart muscle disease associated with severe global left ventricular dysfunction (also termed cardiomyopathy). Other less common forms of symptomatic heart disease in HIV-1-infected patients are pericardial effusion with cardiac tamponade, high-grade arrhythmia with sudden cardiac death, and systemic embolization caused by nonbacterial thrombotic endocarditis or infective carditis. The demographic and clinical characteristics of HIV-infected patients who develop cardiomyopathy as well as potential enhancing risk factors are as yet poorly characterized. This review briefly describes the various presentations and potential causes of symptomatic HIV-related heart disease and discusses the challenge facing clinicians who evaluate HIV-infected patients presenting with serious cardiac manifestations of their disease.

Elevation of plasma thioredoxin levels in HIV-infected individuals.

Thioredoxin (Trx), a ubiquitous protein intimately involved in redox and protein disulfide reductions, has been shown to be released from cells and to have cytokine-like activities. In addition, Trx has been implicated in the redox regulation of immunological responses and shown to be deficient in tissues from AIDS patients. In studies presented here, plasma Trx levels were measured by ELISA in plasma samples from HIV-infected individuals (n = 136) and HIV-negative controls (n = 47). To account for the release of Trx into plasma due to hemolysis, the Trx measurements were corrected according to the level of hemoglobin in the plasma sample. Data presented show that, in contrast to tissue Trx levels, corrected plasma Trx levels are significantly higher in HIV-infected individuals than in controls (P < 0.0001). Furthermore, approximately 25% of the HIV-infected individuals studied have plasma Trx levels greater than the highest levels found in controls (37 ng/ml). Detailed multiparameter FACS analysis of peripheral blood mononuclear cells (PBMC) from the infected individuals demonstrates that those with higher plasma Trx levels (37 ng/ml or greater) tend to have lower overall CD4 counts. In addition, increases in plasma Trx levels correlate with decreases in monochlorobimane staining (indicative of lower intracellular glutathione levels in PBMC) and with changes in surface antigen expression (CD62L, CD38 and CD20) that occur in the later stages of HIV infection. These correlations suggest that elevation of plasma Trx levels may be an important component of advanced HIV disease, perhaps related to the oxidative stress that often occurs at this stage.

Mood disorders in HIV infection

Major depression and mania have increased prevalence in HIV-infected patients, particularly in clinical settings and at later stages of disease. Varied rates of major depression have been reported but differences in definition, methods of study, and population may partly explain these differences. We describe the clinical characteristics, assessment and treatment of mood disorders in HIV-infected patients, with emphasis on aspects specific to the setting of HIV infection. Diagnosis and treatment are complicated by medical complexity, stigma and psychosocial stress. Treatment is associated with clinical improvement. Mood disorders are associated with impulsivity, substance abuse, hopelessness, and demoralization, all of which may increase risk for HIV infection. Also, HIV-associated subcortical damage may be a risk factor for mood disorders, which are increased in late stage HIV infection. We discuss the data supporting the thesis that both of these factors may be at work in producing the high rates of moo...

Dilated heart muscle disease associated with HIV infection.

As more effective therapies have produced longer survival times for HIV-infected patients, non-infectious complications of late stage HIV infection such as the development of severe global left ventricular dysfunction (dilated heart muscle disease) have emerged. The demographic and clinical characteristics of HIV-infected patients who develop dilated heart muscle disease as well as potential risk factors are, as yet, poorly characterized. Of 174 patients enrolled in a prospective longitudinal study, a total of nine patients, all with CD4 T cell counts < 200 mm-3, developed symptomatic heart disease (congestive heart failure n = 7, sudden cardiac death n = 1 and cardiac tamponade n = 1); three of these patients developed progressive cardiac dysfunction leading to primary cardiac failure and death. An additional 55 HIV-infected patients referred to our Cardiomyopathy Service were found to have global left ventricular dysfunction, with 84% having New York Heart Association Class III or IV congestive heart failure on presentation. Clinical characteristics associated with severe symptomatic cardiac dysfunction included low CD4 T cell counts, myocarditis associated with non-permissive cardiotropic virus infection on endomyocardial biopsy and persistent elevation of anti-heart antibodies. No relationships to any specific HIV risk factor or opportunistic infection were found. These findings suggest that a severe form of HIV-related dilated heart muscle disease is largely a disease of late stage HIV infection. Virus-related myocarditis and cardiac autoimmunity may play a role in the pathogenesis of progressive cardiac injury. Long-term longitudinal studies of larger HIV-infected cohorts are warranted to identify clinical, behavioral and immunologic risk factors.