Effect of multiple herpesvirus infections on the progression of HIV disease in a cohort of HIV seroconverters

The effects of herpesviruses infection on the progression of HIV disease remain controversial, with some studies showing accelerated progression and others showing no effect. Furthermore, the effect of concurrent infection with more than one herpesvirus on the progression of HIV disease has never been investigated. To this end, the rates of progression of HIV disease were determined after stratifying for the presence of up to five different herpesvirus infections. The study population consisted of 359 HIV-infected persons for whom the date of seroconversion was estimated (part of the Italian Seroconversion Study). One serum sample from each participant was tested for antibodies to five herpesviruses: HSV-2, CMV, HHV-6, HHV-7, and HHV-8. Univariate analysis showed that HSV-2 and HHV-8 were significantly associated with progression to AIDS, yet when adjusting for age at HIV seroconversion and for the presence of the other herpesvirus infections, only HHV-8 infection showed a significant association. The age-adjusted risk of progression to AIDS with Kaposi's sarcoma increased with the number of herpesvirus infections and was significant in individuals with four infections. The risk of progression to AIDS without Kaposi's sarcoma also increased with the number of infections, although not significantly. Similar results were found when considering CD4+ cell count <200 x 10(6) cells/L as the endpoint. Concurrent infection with more than one herpesvirus does not appear to have a significant effect on the course of HIV disease, except for the known association between HHV-8 and Kaposi's sarcoma. However, even after excluding Kaposi's sarcoma from the AIDS-defining endpoints, a slightly increased risk for participants with four herpesvirus infections remained.     

Comparison of serologic responses between Kaposi's sarcoma-positive and -negative men who were seropositive for both human herpesvirus 8 and human immunodeficiency virus

Although the introduction of HAART decreased substantially the incidence of Kaposi's sarcoma (KS), KS remains the most common cancer among individuals infected with human immunodeficiency virus (HIV). To define markers for progression to KS from the asymptomatic infection of human herpesvirus 8 (HHV-8), serologic responses against HHV-8 were compared between KS-negative and -positive men who were seropositive for both HIV and HHV-8. There was no difference in prevalence of detectable neutralizing antibodies between the two groups. The prevalence of anti-ORF73 antibodies among the dual seropositive patients increased in proportion to their risk of KS. In specimens obtained from 11 HIV+ patients at different intervals over a period of 4-12 years, increase of anti-ORF73 antibody titers was observed in the patients who developed KS but not in the patients who did not develop KS. These results suggest that there is a difference in serologic response against ORF73 between the HIV patients with and without KS.     

High seropositivity of IgG and IgM antibodies against cytomegalovirus (CMV) among HIV-1 seropositive patients in Ilorin,Nigeria

BackgroundHuman immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is a major public health problem in sub-saharan Africa. Cytomegalovirus (CMV) has been reported to enhance HIV replication and accelerate the progression of HIV infection to AIDS.ObjectiveThis study reports on the high seropositivity of immunoglobulin (Ig) G and M antibodies against CMV and the risk factors for CMV infection among HIV/AIDS patients in Ilorin, Nigeria.MethodA total of 180 consented HIV-1 seropositive patients (age-range 16–56 years; 108 females and 72 males) were consecutively recruited. Socio-demographic/behavioral data and 5 ml blood samples were collected from each patient. Plasma of each sample was assayed for anti-CMV IgG/IgM using a CMV IgG and IgM Enzyme Linked ImmunoSorbent Assay (ELISA) kit.ResultsTwenty (11.1%) of the 180 HIV-1 seropositive subjects were positive for anti-CMV IgM antibody while 169(93.9%) were positive for anti-CMV IgG antibody. Age, marital status, number of sexual partners, CD4 cells counts and previous history of blood transfusion were the main correlates of CMV seropositivity among these patients. However, occupation, sex, highly active antiretroviral therapy (HAART) were not statistically associated with CMV seropositivity in this study.ConclusionThis study has shown that greater percentages of HIV-1 seropositive patients had active CMV infection. It has further shown that CMV is hyperendemic in HIV-1 seropositive patients in Ilorin, Nigeria.     

The natural history of transfusion-associated infection with human immunodeficiency virus. Factors influencing the rate of progression to disease

Patients infected by the human immunodeficiency virus (HIV) as a result of blood transfusions are unique in that their dates of infection are well defined and their medical conditions before infection are known. To characterize the natural history of transfusion-associated HIV infection, we studied 694 recipients of blood from 112 donors in whom AIDS later developed and from 31 donors later found to be positive for HIV antibody. Of the recipients tested, 85 were seronegative, 116 were seropositive, and 19 had AIDS. Of 101 HIV-seropositive recipients followed for a median of 55 months after infection, 54 had Centers for Disease Control Class IV disease, including 43 with AIDS. Life-table analysis suggested that AIDS will develop in 49 percent of infected recipients (95 percent confidence limits, 36 to 62 percent) within seven years after infection. As compared with recipients without AIDS, the 43 recipients with AIDS had received more transfusions at the time of infection (median, 21 vs. 7; P = 0.01). HIV-infected blood donors in whom AIDS developed were grouped according to whether AIDS developed within 29 months (the median) after donation (Group 1) or 29 or more months after donation (Group 2). As compared with the 31 recipients of blood from Group 2 blood donors, the 31 recipients of blood from Group 1 donors were more likely to have AIDS four years after infection (49 percent vs. 4 percent; P = 0.005) and illnesses resembling acute retroviral syndrome (14 of 24 vs. 5 of 22; P = 0.03). We conclude that most recipients of HIV-infected blood become seropositive, that AIDS develops in about half these recipients within seven years, and that the risk may be higher when AIDS develops in the blood donor soon after donation.     

Lymph node pathology of acquired immunodeficiency syndrome (AIDS)

There has been a recent notable increase in the number of patients in the United States seropositive for the human immunodeficiency virus (HIV) and also an increase in the number of otherwise healthy homosexuals with persistent generalized lymphadenopathy (PGL). Lymphoid tissue appears to be a favorite target for the initial viral infection, subsequent opportunistic infections, and associated neoplasms. Therefore, evaluation of PGL is important in understanding the nature of the disease. Biopsies of the acquired immunodeficiency syndrome (AIDS) lymph nodes show a spectrum of abnormal lymphoid proliferations, eventual lymphoid depletion, Kaposi's sarcoma, and malignant lymphoma. Although the individual features of AIDS-related lymphadenopathy may not be specific, the constellation of histologic, immunologic, ultrastructural, and fine needle aspiration findings is characteristic.     

The Chicago AIDS autopsy study: opportunistic infections, neoplasms, and findings from selected organ systems with a comparison to national data. Chicago Associated Pathologists

The Chicago acquired immunodeficiency syndrome (AIDS) autopsy study evaluated the first 38 AIDS autopsies through January 1, 1985 from 14 participating institutions in the Chicago area. A complete analysis of neoplasms and opportunistic infections from this material as well as a discussion of pathologic features that may be associated only with human immunodeficiency virus (HIV) infection is presented and compared with national data. Among the neoplasms nodular Kaposi's sarcoma was present post-mortem in only 15.8% of cases as compared with a national autopsy incidence of approximately 50%. This figure was highly significant (Z = -5.439 where significance occurs at more than +/- 1.96) and indicates that the Chicago AIDS population is distinct from the national AIDS population in terms of Kaposi's sarcoma. There were no parallel differences in possible cofactors to account for this lower incidence in Chicago. Inflammatory Kaposi's sarcoma was present in 3 cases but did not approach the near 100% figure reported by others. A discussion of this entity and possible reasons for confusion in its diagnosis are discussed. Chicago continues to have a low incidence of AIDS for a large metropolitan area (308 cases/million population) and a continuing low incidence of nodular Kaposi's sarcoma reported clinically. We hypothesize that either some as yet unidentified agent, not generally present in the Chicago population at risk for AIDS, is responsible for the initiation of Kaposi's sarcoma or that the particular HIV-1 isolate in Chicago is not associated with this malignancy.     

Recombinant human gamma interferon enhances in vitro activation of lymphocytes isolated from patients with acquired immunodeficiency syndrome.

Decreased responses to antigens and lectins are a characteristic feature of peripheral blood lymphocytes isolated from patients with the acquired immunodeficiency syndrome (AIDS). The in vitro addition of recombinant gamma interferon (IFN-gamma) to cultures of peripheral blood lymphocytes obtained from patients with AIDS resulted in an augmented proliferative response [( 3H]thymidine uptake) to phytohemagglutinin (PHA) and an enrichment in CD4+ and CD8+ T lymphocytes. In AIDS cultures stimulated with PHA, IFN-gamma increased the release of T-cell growth factors and enhanced the expression of interleukin-2 receptors on activated lymphocytes. Responsiveness to PHA was augmented, albeit to a lesser extent, by IFN-gamma in cultures derived from normal donors. Proliferation to microbial antigens including herpes simplex virus, cytomegalo virus, and Candida albicans was increased by IFN-gamma in cultures established from a group of AIDS patients with Kaposi's sarcoma who had no history of opportunistic infection.     

Mucosal shedding of human herpesvirus 8 in men

BACKGROUND: Epidemiologic studies suggest that human herpesvirus 8 (HHV-8) is sexually transmitted among men who have sex with men; however, the mode of transmission is unclear. METHODS: To evaluate the patterns of shedding of HHV-8, we obtained mucosal-secretion samples from a cohort of HHV-8-seropositive men who had sex with men and had no clinical evidence of Kaposi's sarcoma. Quantitative polymerase-chain-reaction (PCR) assays, in situ PCR assays, and in situ RNA hybridization were used to identify potential sources of infectious HHV-8. RESULTS: We detected HHV-8 in at least one mucosal sample from 30 of 50 men who were seropositive for HHV-8 (60 percent). Overall, HHV-8 was detected in 30 percent of oropharyngeal samples, as compared with 1 percent of anal and genital samples (P<0.001). In 39 percent of the HHV-8-seropositive men, HHV-8 was detected in saliva on more than 35 percent of the consecutive days on which samples were obtained. The median log titer of HHV-8 from the oral cavity was approximately 2.5 times as high as the titer at all other sites. In situ hybridization studies indicated that HHV-8 DNA and messenger RNA were present in oral epithelial cells. Among 92 men who had sex with men and who were seronegative for the human immunodeficiency virus (HIV), a history of sex with a partner who had Kaposi's sarcoma, deep kissing with an HIV-positive partner, and the use of amyl nitrite capsules ("poppers") or inhaled nitrites were independent risk factors for infection with HHV-8. CONCLUSIONS: Oral exposure to infectious saliva is a potential risk factor for the acquisition of HHV-8 among men who have sex with men. Hence, currently recommended safer sex practices may not protect against HHV-8 infection.     

Human immunodeficiency virus infection in women: report of 102 cases

We examined surgical specimens from 19 human immunodeficiency virus (HIV) seropositive females and 83 females with acquired immunodeficiency syndrome (AIDS) to determine (a) frequency of opportunistic infections (OI) and malignancies, (b) differences or similarities between different risk groups, and (c) differences or similarities when compared with men having AIDS. A risk factor was identified in 86 patients (72 AIDS and 14 HIV seropositive), of whom the majority were intravenous drug abusers (IVDA) (74%) or had had heterosexual contact with a person with AIDS or at risk for AIDS (20%). The remaining patients were blood transfusion recipients or Haitians. All females were treated at Bellevue hospital, a large municipal inner city hospital. The conclusions of our study are as follows. (a) Women with AIDS develop the same type and incidence of OI and lymphomas as the general AIDS population. (b) The incidence of Kaposi's sarcoma in females with AIDS is similar to that seen in male heterosexuals with AIDS. A greater than expected number of epithelial malignancies were found in our population. Characteristics of these carcinomas included young age of the patients (average age of 40), unusually aggressive nature of the tumors, and tendency to occur prior to development of AIDS. We therefore suggest HIV testing in all young females (and males) who present with an unusual or particularly aggressive epithelial neoplasm. (c) The most common OI was Pneumocystis carinii pneumonia (PCP), followed by mycobacterial infections. PCP was seen in a significantly greater percentage of females with a sexual contact risk than in female IVDA (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antibody-dependent cellular cytotoxicity (ADCC)-mediated destruction of human immunodeficiency virus (HIV)-coated CD4+ T lymphocytes by acquired immunodeficiency syndrome (AIDS) effector cells

The acquired immunodeficiency syndrome (AIDS) is defined in clinical terms by the development of Kaposi's sarcoma and/or severe opportunistic infections in persons without predisposing conditions. A hallmark of the syndrome has been a decrease in the number of CD4⁺ T helper cells. The reduction in the frequency of the CD4⁺ lymphocytes has been postulated to be primarily the result of human immunodeficiency virus (HIV) tropism and cytophathogenicity for the T-cell subset. Yet only a small percentage of cells is actually infected with HIV. Recently, we provided evidence indicating that AIDS patients' natural killer cells can mediate normal levels of antibody-dependent cellular cytotoxicity (ADCC) despite exhibiting a defect in natural killer (NK) effector function (J Immunol 139:55, 1987). This finding prompted us to investigate whether AIDS patients' effector cells could mediate ADCC against circulating CD4⁺ T cells infected with or expressing HIV antigen. The findings reported herein demonstrate that AIDS effector cells can mediate lysis of CEM (CD4⁺ T-cell line) coated with HIV protein in the presence of HIV-specific antibody. Lysis was specific, as non-HIV-coated CEM or the addition of HIV-negative serum resulted in no lysis. We then examined HIV-coated peripheral blood-derived CD4⁺ T lymphocytes as targets in ADCC. We demonstrate that in the presence of HIV-specific antibody, HIV-coated CD4⁺ T lymphocytes serve as targets for ADCC by AIDS effector cells. The lytic activity obtained with AIDS effector cells was comparable to that obtained with normal effector cells. These results demonstrate that AIDS effector cells can mediate ADCC against HIV-coated CD4⁺ T lymphocytes and suggest that ADCC may play a rolein vivo in the pathogenesis of AIDS.     

Autopsy findings in AIDS — A histopathological analysis of fifty cases

Summary Fifty consecutive AIDS autopsy cases were evaluated. All subjects showed one or more opportunistic infections and malignancies included in the AIDS case definition with cytomegalovirus and Kaposi's sarcoma being most prevalent. Mycobacterial and cryptococcal infections occurred only infrequently. Most patients of our series after successful treatment ofPneumocystis carinii pneumonia or cerebral toxoplasmosis later succumbed to less treatable conditions like disseminated cytomegalovirus or fungal infections or malignant lymphoma. In the absence of specific treatment for the HIV infection leading to these lethal complications special emphasis must be put on the prevention of HIV transmission and spread.Abbreviations AIDS Acquired immune deficiency syndrome - CDC Centers for Disease Control - CMV Cytomegalovirus - CNS Central nervous system - HIV Human immunodeficiency virus - KS Kaposi's sarcoma - ML Malignant lymphoma - PCP Pneumocystis carinii pneumonia     

Treatment of atypical leishmaniasis with interferon γ resulting in progression of Kaposi's sarcoma in an AIDS patient

Visceral leishmaniasis (kala-azar) affecting HIV-infected patient is being reported in increasing frequency. A 40-year-old German bisexual patient with full-blown AIDS is described who presented with Kaposi's sarcoma, epigastric pain, diarrhea, and weight loss but without fever.Leishmania amastigotes were initially found in biopsies from stomach, duodenum, and a cutaneous Kaposi's sarcoma lesion but were later also recovered from bone marrow and lymph node. The patient received three courses of a combination of pentavalent antimony and interferon-. In addition to the common side effects such as fever, thrombocytopenia, and elevated amylase and lipase, a vivid progression of the Kaposi's sarcoma was noted. Tumor progression was temporally closely associated with treatment with interferon-. Because this phenomemon has also been observed in other patients, we advise caution when using interferon- in patients with Kaposi's sarcoma.Abbreviations AIDS acquired immunodeficiency syndrome - HIV human immunodeficiency virus - KS Kaposi's sarcoma Correspondence to: H. Albrecht     

Pathogenetic role of HIV infection in Kaposi's sarcoma of equatorial East Africa

Thirty residents of north-central Tanzania with various forms of Kaposi's sarcoma (KS) were evaluated. The absolute number of peripheral blood OKT4 lymphocytes in patients and Tanzanian control subjects tended to be low (in comparison with healthy young American adults), and many had inverted T4/T8 ratios. Plasma polyclonal beta- and gamma-globulin concentrations were increased in many patients with KS and in control patients in Tanzania with chronic dermatopathies, but not in African hospital employees and patients undergoing elective surgery. Three of nine patients with locally aggressive KS possessed antibodies to human T-cell lymphotropic virus type III/lyphadenopathy-associated virus (HIV), but none had evidence of the acquired immunodeficiency syndrome (AIDS) or the AIDS-related complex. Three patients with disseminated, rapidly progressive KS and high HIV-antibody titers had an immunologic and clinical picture consistent with AIDS. Two of 13 patients with the classic plaque/nodular form of KS had low plasma titers of HIV antibody, but the significance of these serologic findings is not known. The evidence suggests that HIV plays a role in the pathogenesis of some cases of KS in East Africa, but most patients with KS in East Africa have no evidence of overt immunologic deficiency or HIV infection.     

AIDS virus infection in Nairobi prostitutes. Spread of the epidemic to East Africa

The acquired immunodeficiency syndrome (AIDS) is epidemic in Central Africa. To determine the prevalence of AIDS virus infection in East Africa, we studied 90 female prostitutes, 40 men treated at a clinic for sexually transmitted diseases, and 42 medical personnel in Nairobi, Kenya. Antibody to human T-cell lymphotropic virus Type III (HTLV-III) was detected in the serum of 66 percent of prostitutes of low socioeconomic status, 31 percent of prostitutes of higher socioeconomic status, 8 percent of the clinic patients, and 2 percent of the medical personnel. The presence of the antibody was associated with both immunologic and clinical abnormalities. The mean T-cell helper/suppressor ratio was 0.92 in seropositive prostitutes and 1.82 in seronegative prostitutes (P less than 0.0001). Generalized lymphadenopathy was present in 54 percent of seropositive prostitutes and 10 percent of seronegative prostitutes (P less than 0.0001). No constitutional symptoms, opportunistic infections, or cases of Kaposi's sarcoma were present. Our results indicate that the epidemic of AIDS virus infection has, unfortunately, spread extensively among urban prostitutes in Nairobi, Kenya. Sexual exposure to men from Central Africa was significantly associated with HTLV-III antibody among prostitutes, suggesting transcontinental spread of the epidemic.     

The emerging AIDS epidemic in Ireland--clinicopathological findings in 23 early cases

A longitudinal study with follow up to the end of 1989 was carried out on 23 patients with AIDS who had attended St. James's Hospital, Dublin, by the end of 1987. Until then only 33 cases of AIDS had been reported in Ireland. The patients, all of whom had antibodies to human immunodeficiency virus (HIV), were predominantly male, young (mean age 31.3 years) and belonged about equally to three major risk groups: homosexuals, intravenous drug abusers (IVDA) and haemophiliacs. AIDS was diagnosed because of oesophageal candidiasis (8 cases), Kaposi's sarcoma (4), mycobacterial infection (4), pneumocystis carinii pneumonia (3), toxoplasmosis (2) or encephalopathy (2). Malignant lymphoma and a variety of infections occurred in the course of illness, and neurological involvement developed in 11 patients (48%). Mortality following diagnosis of AIDS was 39% at one year and 64% after two years. Autopsy in 10 of the 16 deaths contributed much to defining the extent and nature of the disease. The demographic pattern, risk group status, survival and range of complications were broadly similar to the pattern of AIDS as seen elsewhere in developed countries. However, compared to the profile of disease reported from the United States, oesophageal candidiasis (52%) and Mycobacterium tuberculosis (22%) were more prominent, pneumocystis carinii pneumonia (39%), Kaposi's sarcoma (22%) and Mycobacterium avium intracellulare (13%) were less frequent and cryptococcal infection was not identified. These regional variations in the frequency of the various complications and particularly the prominence of tuberculosis, probably reflect the interaction of the immunocompromised patient with the local environment and may have important diagnostic and therapeutic implications.     

Kaposi''s sarcoma among AIDS patients: Transmissible venereal tumour by cell engraftment?

The epidemiologic findings of Kaposi's sarcoma (KS) among patients with the acquired immunodeficiency syndrome (AIDS) suggest that human immunodeficiency virus (HIV) infection is insufficient for the development of KS. It was speculated that another sexually transmitted infection is responsible for the markedly increased incidence of KS among patients who acquired HIV infection through sexual intercourse. However, no such contributing infectious agent was consistently identified. The canine transmissible venereal tumour (TVT) is a malignant tumour that can be transplanted by viable cells across major histocompatibility complex (MHC) barriers. Recent findings suggest that all canine TVTs originated from the same tumour and were transferred from one animal to the other during sexual intercourse. It is suggested that, in analogy with the canine TVT model, the characteristics of KS epidemic among AIDS patients may be explained by transmission and engraftment of viable malignant cells during intercourse.     

The prevalence of infection with human immunodeficiency virus over a 10-year period in rural Zaire

In 1985 we tested 659 human serum samples, collected in the remote Equateur province of Zaire in 1976, for antibody to human immunodeficiency virus (HIV). Five (0.8 percent) were positive, and HIV was isolated from one of these. Follow-up investigations in 1985 revealed that three of the five seropositive persons had died of illnesses suggestive of acquired immunodeficiency syndrome (AIDS), and two remained healthy but seropositive. In 1986, a serosurvey we conducted using a cluster-sampling technique in the same region showed a seroprevalence of 0.8 percent in 389 randomly selected residents. The seroprevalence in 283 prostitutes was 11 percent. Patients with AIDS were identified in various hospitals in the province. Risk factors for AIDS included a greater than average number of sexual partners and residence outside the area. We believe that the long-term stability of HIV infection in residents of rural Zaire suggests that social change may have promoted the spread of AIDS in Africa.     

Delayed hypersensitivity skin testing and anergy in a population of gay men

Anergy is almost universal among patients with the acquired immunodeficiency syndrome (AIDS). To determine the prevalence and correlates of anergy in a population at risk for AIDS, we performed skin tests in 1120 gay men who were enrolled in a prospective study of the natural history of human immunodeficiency virus (HIV) infection. Anergy, defined as no induration to any of four intradermal antigens, was present in 12%. Individually, no induration was detected in response to tetanus toxoid (41%), mumps (28%), candida (47%), and trichophyton (72%). Anergy was strongly associated with the presence of antibody to HIV and with a reduced number of T helper lymphocytes, but not independently with generalized lymphadenopathy, the number of reported male sexual partners in the previous 2 years, the number of T suppressor lymphocytes, or with high titers of antibodies to cytomegalovirus. Nine percent of HIV antibody-negative subjects and 20% of antibody-positive subjects were anergic; anergy is not specific for serologically documented HIV infection in this population. Skin testing with only tetanus toxoid, candida, and mumps antigens may be sufficient to detect anergy. In the presence of HIV antibody, the ability of anergy to predict progressive immunodeficiency remains to be determined.     

Accessory cell function in asymptomatic human immunodeficiency virus-infected patients

Peripheral blood mononuclear cells from human immunodeficiency virus seropositive (HIV+) individuals who did not exhibit symptoms of acquired immunodeficiency syndrome (AIDS) (Walter Reed Stage 1 patients) were tested for accessory cell function for presentation of recall antigens to autologous T lymphocytes and for presentation of HLA alloantigens to T lymphocytes from healthy, HIV- donors. Neither experimental model indicated a defect in accessory cell function at this early stage after HIV infection, although our study does not exclude the possibility of accessory cell dysfunction at a later stage of AIDS development.     

Human Herpesvirus 8 and Protection from AIDS Dementia Complex

Infection with human herpesvirus 8 (HHV-8) has been associated with the development of three distinct conditions: Kaposi's sarcoma, body cavitybased lymphoma and Castleman's disease. HHV-8 produces chemokinelike proteins including viral macrophage inflammatory protein II, which has been shown to block human immunodeficiency virus 1 (HIV-1) infection of CD4-positive cells expressing CCR-3. As CCR-3 is a receptor for HIV-1 into microglial cells, it has been hypothesized that HHV-8 infection may inhibit HIV-1 infection of the brain, thereby decreasing the incidence of AIDS dementia complex. We reviewed published studies of the incidence of AIDS dementia complex in individuals with and without Kaposi's sarcoma. The data are consistent in showing a negative association between Kaposi's sarcoma and AIDS dementia complex and, although sparse, support the hypothesis that productive HHV-8 infection decreases HIV-1 infection of the brain sufficiently to decrease the incidence of AIDS dementia complex. This negative association should be examined in further cohorts of HIV-1-infected subjects, to exclude alternative explanations.