Late-stage HIV Infection Research Articles

CD8+Cell Noncytotoxic Anti-HIV Response: Restoration by HAART in the Late Stage of Infection

Highly active antiretroviral therapy (HAART) is currently the best HIV infection management strategy. However, its effects on the CD8+ T cell noncytotoxic anti-HIV response (CNAR) are not well known. We investigated if HAART has different effects on CNAR in patients at the intermediate and late stages of HIV infection. Untreated healthy HIV-infected subjects with a mean CD4+ T cell count of 606 cells/microl were examined as a reference group. Plasma viral load, CD4+ T cell count, and CNAR activity were measured at baseline and regular intervals for at least 48 weeks following initiation of HAART. Baseline CNAR activity in all subjects correlated inversely with viral load and directly with CD4 T+ cell counts. The level of CNAR in the latestage group was significantly lower than in the intermediate-stage and the healthy reference group (p < 0.01). Following initiation of HAART, substantial increases in CD4+ T cell counts and decreases in viral loads were observed in both groups, indicating treatment success. CNAR activity was found to be increased significantly during HAART, but only in the late-stage group (p < 0.01). This increase in CD8+ cell function was seen within 4 weeks of treatment initiation and resulted in levels of CNAR activity almost equal to those observed in the healthy reference subjects. Our findings suggest a beneficial effect on CNAR in those individuals with reduced activity, typically in late-stage infection.

IL‐2 and IL‐10 serum levels in HIV‐1‐infected patients with or without active antiretroviral therapy

We analyzed IL-2 and IL-10 serum levels in 26 HIV-1-infected patients naive of antiretroviral treatment and in 34 patients receiving highly active antiretroviral therapy (HAART). All patients without treatment were asymptomatic. When they were stratified according to levels of CD4+ T cells, IL-2 levels were significantly increased in patients with > or =200 CD4+/microl and IL-10 levels were significantly increased in patients with <200 CD4+/microl compared to controls. A significant negative correlation was observed between IL10 levels and CD4+ T-cell counts. No correlation was observed between IL-2 and IL-10 levels and viral load due to the wide range of variability in the number of HIV copies/ml present in the different patients. However, IL-2 levels were higher in patients with high viral load than in patients with low viral load. In patients with HAART, IL-2 and IL-10 levels were similar to the control group and no differences were detected respecting CD4+ T cells counts and viral load. Our findings show that the modifications in IL-2 and IL-10 serum levels in HIV-1-infected patients naive of antiretroviral treatment are associated with the progression of immunological damage. Furthermore, they show a dysbalance of type-1/type-2 cytokines with an involvement of type-2 cytokines in later stages of HIV infection. Cytokine dysregulation can be reversed by HAART in the context of immune restoration and viral suppression.

Effect of a liquid nutritional supplement on viral load and haematological parameters in HIV-positive/AIDS patients

The effect of a nutritional supplement on the immune status and haematological parameters of HIV-positive/ AIDS patients is tested using standard procedures. This clinical trial of 35 patients consists of a baseline visit and three months of supplementation from April to September 2003. Results showed that viral load decreased significantly (P<0.002) with time following supplementation. Mean cell volume (MCV) and mean cell haemoglobin concentration (MCHC) increased significantly (P<0.002 and P<0.0002, respectively), reflecting the positive effect of the supplement on these haematological parameters. Supplementation had no effect on CD4+ T-cell count, which decreased significantly with disease progression. Owing to certain limitations of the study (small sample size, short duration and the late stage of HIV infection), further studies are needed to confirm the effect attributed to the supplement.

Apoptosis of CD57+ and CD57− lymphocytes in the lung and blood of HIV-infected subjects

Patients infected with HIV frequently have a CD8+ lymphocytic alveolitis consisting of HIV-specific CD8+CD57− cytotoxic T lymphocytes. However, in late stage disease, there is expansion of a CD8+CD57+ population with suppressive properties. We examined role of lymphocyte apoptosis in the expansion of the CD8+CD57+ lymphocytes in late stage HIV in the lung and blood compartment in human subjects. Fas was expressed on virtually all lung lymphocytes from HIV-infected and normal subjects. Fas ligand expression was increased in HIV infection in both CD8+CD57+ and CD8+CD57− lymphocytes, though a significantly greater percentage of CD8+CD57+ cells expressed this marker. CD8+CD57+ lymphocytes in normal and HIV-infected subjects underwent more apoptosis than CD8+CD57− cells. However, in late stage HIV infection, the percentage of CD8+CD57+ cells undergoing apoptosis declined. These data demonstrate that under normal conditions CD8+CD57+ cells appear destined to undergo programmed cell death. Expansion of suppressive CD8+CD57+ cells in the lungs of HIV-infected subjects with advanced disease may be due to the failure of this normal regulatory process.

Herpes zoster in HIV-1-infected patients in the era of highly active antiretroviral therapy: a prospective observational study

Between June 1994 and May 2003, 93 of 716 (13.0%) HIV-infected patients with a median baseline cell differentiation CD4+ count of 61 x 10(6) cells/L (range, 1-1206 x 10(6) cells/L) developed 103 episodes of herpes zoster [HZ], with an incidence of 5.67 per 100 person-years (PY). The incidence of HZ in the pre-highly active antiretroviral therapy (HAART) era (17.21 per 100 PY) was significantly higher than that in the post-HAART era (5.05 per 100 PY) (P < 0.0001). In the first six months of enrollment, the incidence of HZ was significantly higher than that between six and 12 months both in the pre-HAART (27.65 per 100 PY versus 8.43 per 100 PY, P = 0.02) and post-HAART era (17.79 per 100 PY versus 3.39 per 100 PY, P < 0.0001). In multivariate analyses, only baseline CD4+ count remained a significant risk factor associated with HZ. HZ did not increase mortality rate either in the pre-HAART or post-HAART era, although the risk for HIV progression was significantly higher in patients with HZ (adjusted odds ratio [OR], 1.747, 95% confidence interval, 1.037-2.943). We conclude that the incidence of HZ was highest in the first six months of enrollment in patients at late stage of HIV infection, which did not increase with the introduction of HAART. Baseline CD4+ lymphocyte count was the most significant risk factor associated with development of HZ. HZ was associated with increased risk for HIV progression, but not mortality.

Prevalence of Toxoplasma gondii infection and incidence of toxoplasma encephalitis in non-haemophiliac HIV-1-infected adults in Taiwan

We assessed the seroprevalence of Toxoplasma gondii infection and incidence of toxoplasma encephalitis (TE) in 844 non-haemophiliac HIV-infected patients in Taiwan between June 1994 and April 2003. Approximately 70% (69.3%) of them had a baseline CD4+ lymphocyte count of 200 x 10(6)/L or less, and more than 70% (73.9%) having initiated highly active antiretroviral therapy. The seroprevalence of T. gondii infection was 10.2%, which did not differ with sex,age,route of transmission, birth inside or outside of Taiwan, or CD4+ lymphocyte stratifications. After a median observation duration of 603 days (range, 1-3264 days), 10 (1.2%) patients developed 11 episodes of TE after a median interval of 30 days (range, 1-941 days) between enrolment and diagnosis of TE, with an incidence of 0.59 per 100 person-years (PY) (95% confidence interval, 0.56-0.63 per 100 PY). We concluded that the incidence of TE of HIV-infected patients in Taiwan was lower than that reported in western countries because of a lower seroprevalence of T. gondii infection and use of antimicrobial prophylaxis and antiretroviral therapy, although most of the patients were at the late stage of HIV infection.

Study of patients diagnosed with advanced HIV in the HAART era – OMEGA Cohort

Our objective is to analyse patients diagnosed with late-stage HIV infection in the highly active antiretroviral therapy (HAART) area. A prospective, observational study of all patients with an initial CD4 < 50 x 10(6)/L was carried out. Epidemiological, clinical and HAART-associated data were analysed. Survival rates were estimated and pairs of survival curves were compared. The statistical program used was SPSS (version 10). In all, 349 HIV-infected patients were diagnosed, 117 (33.5%) had late-stage disease, mean CD4 23.9 x 10(6)/L and mean viral load (VL) 5.38 log10. In 98 men, mean age 39.5 years, percentage of AIDS cases at their first attendance was 83.8%. The median follow-up period was 28 months and 27 died. Pneumocystis carinii was the most frequent cause of AIDS (24.4%) and death (18.5%). Survival rates at 12, 24 and 36 months were 95.6%, 85.8% and 72.4%. HAART was started in 82.1%. VLs < 50 copies/mL at one, two and three years of treatment were 55.2%, 55.7% and 58.0%. Resource utilization included 0.58 hospitalization/patient/year and 0.07 events/patient/year. HAART-related complications were as follows: 50% lipodystrophy, 9.7% hypertension, 22.2% hyperglycaemia, 26.4% hypercholesterolaemia, 31.9% hypertrygliceridaemia and 18.1% mixed hyperlipaemia. Over one-third of our patients have advanced HIV infection at diagnosis. However, the outcome is favourable, with a good immunovirological response and few new opportunistic events. HAART-related complications were frequent.

The imperative for family planning in ART in Africa

A massive and extremely ambitious initiative is underway to provide antiretroviral therapy to millions of patients with HIV in the developing world especially Africa very quickly. Recognising the need for simplicity in such resource-poor settings WHO guidance calls for one of four first-line tripletherapy alternatives—each with two nucleoside reverse-transcriptase inhibitors (NRTIs) and one non-nucleoside reverse-transcriptase inhibitor (NNRTI). In addition to supplying antiretrovirals in mass amounts major challenges include: identifying willing patients at the later stages of HIV infection when antiretroviral therapy is appropriate; overcoming AIDS-related stigma; ensuring adherence to the regimens; and providing sustained care and follow-up. In the middle of efforts to provide antiretrovirals rapidly on such a grand scale important needs such as family planning risk being overlooked. However ensuring that contraception is available to women on antiretrovirals is crucial— not only for the well-being of women and children but also as a potent instrument to combat AIDS. In Africa HIV is mostly transmitted heterosexually and women are somewhat more likely to be infected than men. Although women of reproductive age make up about 20% of the population they are 53% of the HIV-infected population. Therefore as the provision of antiretroviral drugs advances we must pay heed to important problems facing women. (excerpt)

Perceived psychosocial needs, social support and quality of life in subjects with HIV/AIDS

The psychosocial needs, social support, quality life and adjustment of subjects with HIV/AIDS were assessed using a self-report instrument with 40 items and a Cronbach's alpha coefficient of 0.74. Eighteen patients at varying stages of HIV infection who knew their sero-status served as subjects. Results showed that the needs perceived as most important by HIV/AIDS patient were not met by their most valued sources of social support. Fifteen (83.3%) subjects expressed dissatisfaction with the quality and quantity of support received since the diagnosis of HIV/AIDS, 12 (66.7%) reported poor social adjustment to the diagnosis, 11 (61.2%) reported low quality of life/wellbeing and 8 (44.4%) reported severe lifestyle changes caused by the disease. Perceived social dysfunction was in four areas – fear of stigma in 15 (83.3%) subjects, lack of satisfying relationship with family in 15 (83.3%) subjects, lack of inner motivation in 12 (66.7%) subjects and social isolation in 12 (66.7%) subjects. Subjects with extrovert personality perceived significantly more lifestyle changes, reported a higher fear of rejection and a lower degree of adjustment to the disease than subjects with introvert personality. Subjects with late-stage HIV infection reported a lower social adjustment to the disease, a lower quality of life and more severe lifestyle changes. Satisfaction with social support correlated significantly with quality of life and social adjustment. It is therefore concluded that the higher the level of satisfaction with social support, the higher the quality of life and social adjustment to HIV/AIDS. The health worker should therefore harness and encourage the provision of qualitative social support for people living with HIV/AIDS. Keywords – Psychosocial needs, Quality of life, Social support. Global Jnl Medical Sciences Vol.2(2) 2003: 171-175

1003. HIV-1-Derived Lentivirus Vector-Based Antisense Gene Therapy: Towards an Alternative Treatment for HIV/AIDS

Despite the significant advancement in HIV/AIDS treatment with highly active antiretroviral therapy (HAART), HIV/AIDS remains incurable. Limitations of HAART include expense, disabling complications, and a stringent requirement for compliance. In the United States, where HAART has become the standard of care, approximately 20% of newly transmitted virus is already resistant to at least one antiretroviral drug. In anticipation of expanded HAART in Africa, there is concern regarding rapid emergence of drug resistant strains of HIV that brings into question HAART as a long-term solution. We have developed an alternative therapy for HIV/AIDS therapy using an HIV-1-based lentiviral vector expressing a 937-base antisense gene against the HIV envelope, VRX496, for autologous T cell therapy. T cells are transduced with vector in the presence of co-stimulatory CD3/CD28 beads, and subsequently expanded in culture. Preclinical studies demonstrated the feasibility of this approach in normal CD4+ T cells and inCD4+ T cells isolated from 20 early and late stage patients, as defined by viral loads. An efficient gene transfer procedure was established, which demonstrated stable transfer rates of 94% +/- 5%. Antisense inhibited HIV in cultures by >93% over mock transduced controls, regardless of patient status or the tropism of the infecting virus. A Phase I open label non-randomized clinical trial was then initiated to investigate the safety and tolerability of autologous T cells modified with VRX496. In this study, 5 HAART resistant patients having CD4 T cells counts between 200-500 cells/mm3 are serially enrolled in the study that includes 3-week, and 3 and 6-month monitoring points. Each patient is given approximately 1 1010 modified autologous CD4 T cells in a single dose. Patients are monitored for viral load, CD4 count, emergence of any replication competent lentivirus (RCL), immunological parameters, and clinical indications. Adverse events are defined in part by a sustained 0.5 log increase in viral load, or sustained 0.5 log decrease in CD4 count within 3 weeks post dose. To date, 3 subjects have been infused, and the first and second subjects have completed the 6 and 3-month monitoring points, respectively. No adverse events have been noted, and all RCL assays have been negative. CD4 counts remained steady and engraftment of VRX496-modified cells was observed for at least 6 months in the first patient and 3 months in the second patient. At dosing, subject 1 had an average viral load of 188,500 and subject 2 had an average viral load of 40,428. After three and six months post dosing, subjects 1 and 2 respectively, had viral loads below baseline. This interim analysis supports the promise of lentiviral vectors for late stage HIV infection, and that VRX496 could become a viable treatment modality for individuals infected with HIV/AIDS.

Differential Expression of CXCR4 Receptor in Early and Term Human Placenta

Chemokines and their receptors play a crucial role in regulation of T-cell migration and differentiation. Recent findings suggest that these proteins can also regulate cell functions such as angiogenesis and proliferation. Besides, CXCR4, a chemokine receptor, is one of the two major co-receptors for entry of the HIV virus during the late stages of HIV infection. We have studied the expression of CXCR4 in early (8–10 weeks) and term human placenta. Immunofluorescence staining and RT–PCR analysis revealed a differential expression of the CXCR4 receptor. Densitometric analysis revealed a two fold higher expression of the CXCR4 mRNA in early as compared to term placenta. This finding suggests that the expression of CXCR4 receptor may be developmentally regulated and its role in the early stages of pregnancy is implicated, when embryogenesis and organogenesis takes place. The fact that only 1–2 per cent of the placental transmission of the HIV virus takes place in the early placenta may also be correlated with our findings, suggesting that CXCR4 may not have a direct role in the transmission of HIV infection in the placenta.

MAC Infection: 3 Drugs Better Than 2?

Disseminated Mycobacterium avium complex (MAC) disease occurs frequently during late-stage HIV infection. Current guidelines propose therapy with

Eyelash length in HIV-infected patients.

Acquired trichomegaly of the eyelashes in HIV-infected patients usually appears at the late stage of HIV infection. Eyelash length was measured in a series of 204 HIV patients, and no correlation with CD4 cell count, viral load, Centers for Disease Control and Prevention category, and AIDS case criteria was established. Our data support the finding that eyelash trichomegaly is currently uncommon in HIV-infected patients, perhaps because of antiretroviral therapy or an improvement in their immune situation.

Increased in vitro cytopathicity of CC chemokine receptor 5-restricted human immunodeficiency virus type 1 primary isolates correlates with a progressive clinical course of infection.

The presence of only non-syncytium-inducing beta-chemokine receptor 5-restricted (R5/NSI) human immunodeficiency virus type 1 (HIV-1) in an infected individual has been associated with long-term asymptomatic survival. However, the majority of R5/NSI HIV-1-infected individuals do progress to AIDS. Here, we compared the replicative capacity and cytopathicity of R5/NSI HIV-1 variants that were isolated early and late in the clinical course from 7 long-term asymptomatic individuals and 7 individuals with progressive HIV-1 infection. R5/NSI HIV-1 cytopathicity in vitro directly correlated with in vitro replication. HIV-1 variants obtained early and late during long-term asymptomatic HIV infection from the same individual were equally cytopathic. In contrast, HIV-1 variants obtained during late-stage progressive HIV infection were more cytopathic than viruses obtained early in infection from the same individuals. Our data indicate that the cytopathicity of HIV-1 variants may increase with progression to disease.

Preliminary development of the World Health Organsiation's Quality of Life HIV instrument (WHOQOL-HIV): analysis of the pilot version

The assessment of quality of life (QoL) is central to understanding how people's lives are affected by HIV infection. A reliable and valid measurement tool developed for cross-cultural use will be important in evaluating the global impact of the disease. This paper reports on the development and preliminary assessment of the WHOQOL-HIV pilot instrument that is designed for use with the WHOQOL-100 for persons living with HIV and AIDS (PLWHA). In this study, 900 people with a mean age of 32 from six culturally diverse sites completed the WHOQOL-100 along with 115 HIV specific items. Respondents were HIV asymptomatic (23%), HIV symptomatic (23%), had AIDS (20%) or were well (34%). Analyses to select the best items from the piloted instrument resulted in the inclusion of 33 items covering 12 new facets for a field trial version of the WHOQOL-HIV instrument; e.g. symptoms of HIV, body image, social inclusion, death and dying, and forgiveness. The results indicate excellent internal consistency for the scale ( α=0.98) and its domains ( α=0.87–0.94). For PLWHA, pain and discomfort, positive feelings, dependence on medication, sexual activity, financial resources and spiritual connection were particularly poor, indicating that the severest impact of HIV extends beyond physical well-being to the psycho–social–spiritual and environmental areas of QoL. Comparisons using ANOVA showed that persons who are at later stages of HIV infection, or are currently ill report poorer QoL than those that were well ( p<0.01). Women report poorer QoL than men for almost every facet ( p<0.01) and older persons (>30) reported lower negative feelings, and better social inclusion, spiritual connection, forgiveness and spiritual experience than younger persons. Finally, those with no education, or only primary education showed some of the poorest means. It is concluded that these new items and facets add value for measurement of QoL in PLWHA.

HIV-associated Guillain–Barré syndrome

Human immunodeficiency virus-associated Guillain–Barré syndrome (HIV-GBS) has been reported since 1985. Based on previous reports, this neuropathy typically occurs early in HIV infection, even at seroconversion, prior to developing acquired immunodeficiency syndrome (AIDS). Patients with GBS and CD4 counts of <50 have been proposed to have cytomegalovirus (CMV) infection and empiric gancyclovir is recommended. We reviewed medical records of 10 patients with HIV-GBS at five hospitals from 1986 to 1999. The mean CD4 count was 367/mm 3 (range 55–800). GBS was the first symptom of HIV infection in three patients. Four patients had AIDS with CD4 counts ranging from 55 to 190. CSF white blood cell (WBC) was 0 wbc/mm 3 in four patients, 2–10 wbc/mm 3 in three and 11–17 wbc/mm 3 in two. Three had recurrent weakness from 9 weeks to 4 years after the onset of symptoms, which persisted. HIV-GBS occurs in early and late stages of HIV infection, and may follow the onset of AIDS. No patients were seen with severe immunosuppression (CD4<50). A mild cerebrospinal fluid (CSF) pleocytosis in GBS suggests HIV infection, but is frequently absent. Compared to HIV-negative people, HIV-GBS may be associated with more frequent recurrent episodes or the development of CIDP.

Zoonotic species of Cryptosporidium are as prevalent as the anthroponotic in HIV-infected patients in Thailand.

The epidemiology of chronic diarrhoea in adults with late-stage HIV infection was investigated in a prospective study in Bangkok, Thailand. During this investigation, 34 Cryptosporidium isolates were obtained from the faeces of 36 patients, with mean CD4(+) counts of only 14 x 10(6) CD4(+) cells/litre (range = 2 x 10(6) - 53 x 10(6)/litre), who had symptomatic cryptosporidiosis. Genotyping of these isolates, by RFLP analysis and DNA sequencing of the hypervariable region of the 18S rRNA gene, indicated that only 17 (50%) were of the C. parvum human genotype. The rest were of C. meleagridis (seven), the C. parvum 'bovine' genotype (five), C. felis (three) and C. canis (two). Extensive genotypic heterogeneity was observed among the C. parvum isolates, and two other isolates, one of C. meleagridis and the other of C. felis, produced atypical restriction patterns and were only identified by sequencing. This appears to represent the first report of C. canis and the 'bovine' genotype of C. parvum in HIV-infected Thai patients.

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.

Clinical manifestation of HIV-related pulmonary hypertension.

In recent years, much more thought has been given to the pathogenic role of HIV and to the clinical manifestations of HIV-related pulmonary hypertension (HRPH), which currently represents one of the most severe events during HIV disease. HRPH occurs in early and late stages of HIV infection and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HRPH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnea that will progress to the point of breathlessness at rest. The diagnosis of HRPH can be made only after all etiologies for pulmonary hypertension have been excluded. Echocardiography has been proven to be an extremely useful tool for diagnosing HRPH, and Doppler echocardiography can be used to estimate systolic pulmonary artery pressure and to monitor the effects of therapy. Assessment of hemodynamic measures by catheterization remains, however, the best test for evaluating response to therapy. Cardiac catheterization is mandatory to characterize the disease and exclude an underlying cardiac shunt as etiology. Vasodilators have been extensively used in the treatment of pulmonary hypertension, since vasoconstriction is a determinant characteristic of this disease. However, HRPH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new, more efficient antiretroviral treatment are introduced, clinicians should expect to encounter an increasing number of cases of pulmonary hypertension in HIV+ patients in the future.

Activity of natural killer cells during HIV-1 infection in Brazilian patients.

Natural killer cells are increasingly being considered an important component of innate resistance to viruses, but their role in HIV infection is controversial. Some investigators have found that natural killer cells do not confer a protective effect during the progression of HIV disease, whereas others have shown that natural killer cells may be protective and retard the progression of the disease, either through their lytic activity or by a chemokine-related suppression of HIV replication. In this study, we analyzed functional alterations in the activity of natural killer cells during HIV-1 infection using a natural killer cells activity assay with K562 cells as targets. Our results show that the activity of natural killer cells decreases only in the advanced phase of HIV infection and when high (40:1) effector cell-target cell ratios were used. The depression at this stage of the disease may be related to increased levels of some viral factors, such as gp120 or gag, that interfere with the binding capacity of natural killer cells, or to the decreased production of natural killer cells -activity-stimulating cytokines, such as IFN-a and IL-12, by monocytes, a subset of cells that are also affected in the late stage of HIV infection. The data suggest that decreased natural killer cells cell activity may contribute to the severe impairment of the immune system of patients in the late stages of HIV infection.