Handzel Zt

Autoantibodies in male homosexuals and HIV infection

We have used ELISA to study the frequency of autoantibodies to several antigens in the serum of 17 male homosexuals (MHS) negative for HIV (HIV-), 11 asymptomatic HIV seropositive MHS (HIV+) and patients with ARC (N = 15) or AIDS (N = 13), and compared them to 20 matched healthy heterosexual controls. Serum antibody binding to histones, cardiolipin, ss-A, ss-B and Sm was found to be significantly higher in each of the MHS groups studied as compared to controls (P less than 0.001), and was also increased in the HIV+ patients vs. the HIV- group (P less than 0.05). In contrast, no increase in autoantibodies to ss-DNA, ds-DNA, poly(I), poly(G) or RNP were found in any of the groups tested. These results enlarge the spectrum of autoimmunity previously reported in HIV infection and identify a similar pattern to a lesser degree, already present in HIV- MHS, suggesting a role for HIV or concomitant virus infections in its pathogenesis.

Possible role of natural cytotoxic activity in the pathogenesis of AIDS

In an attempt to assess the role of immune cytotoxic activity in the sequence of events leading to the acquired immunodeficiency syndrome (AIDS), natural cytotoxic activity was studied in 17 asymptomatic homosexual males, seropositive for anti-human immunodeficiency virus (HIV) antibodies, as compared to 16 of their seronegative counterparts and to 14 control healthy heterosexual individuals. Cell (contact)-mediated cytotoxicity (CMC) as well as cytotoxin (CTX) production by lipopolysaccharide (LPS)-stimulated, phytohemagglutinin (PHA)-stimulated, HeLa tumor cell-stimulated, and unstimulated peripheral blood mononuclear cells (PBMC) were determined using HeLa cell monolayer cultures, sensitized with cycloheximide, as targets. The CMC was markedly enhanced in the seropositive group (28 +/- 21 (mean +/- SD) lytic units/10(6) PBMC) as compared to the seronegative group (17 +/- 7; P less than 0.005) and to the heterosexual group (13 +/- 6; P less than 0.05). Likewise, CTX production by unstimulated PBMC from seropositive homosexuals (19 +/- 26 units/ml) was higher than that observed in the other groups (both 4 +/- 4 units/ml; P less than 0.05). CTX production by PHA-stimulated, LPS-stimulated, and HeLa cell-stimulated PBMC was significantly enhanced in both the seropositive and seronegative groups in comparison to the normal heterosexual controls. These results suggest that increased cytotoxic activity may be present in homosexuals prior to their exposure to HIV, and may be further enhanced after HIV infection.

Immunoreconstitution of T-cell impairments in asymptomatic male homosexuals by Thymic Humoral Factor (THF)

The feasibility of using Thymic Humoral Factor (THF) for immunomodulation in asymptomatic male homosexuals was evaluated in a study on fifteen subjects with T-cell impairments, selected on the basis of a 2SD reduction in T helper/inducer (T4+) cells and one additional lymphocytic defect. Following two biweekly courses of treatment, mean relative increments of T4+ (P less than 0.002), T3+ (P less than 0.02) and total lymphocyte (P less than 0.05) populations of the group receiving THF (n = 7) were significantly increased when compared to the placebo group (n = 8). In addition, a transient increase in T4+ lymphocytes was observed after the first course in the two individuals of the THF-treated group who were seropositive for HTLV-III/LAV but not in those who were seronegative. No difference was found between the groups in fluctuations of serum interferon (IFN) or proliferation of peripheral mononuclear cells to mitogens. The results of this limited trial demonstrate that THF is capable of correcting T-cell impairments that may predispose asymptomatic homosexuals to infection by HTLV-III, without affecting IFN production. These findings suggest that future strategies for AIDS prevention in high-risk groups should include institution of large controlled trials in immunodeficient, asymptomatic, HTLV-III/LAV-seronegative male homosexuals to study the potential of selective immunoreconstitution as a preventive measure against HTLV-III/LAV infection.

In Vitro Effects of Recombinant TNF-α Binding Protein (rTBP-1) on Hematopoiesis of HIV-Infected Patients

Summary: Tumor necrosis factor‐alpha (TNF‐&agr;) is believed to contribute to the hematopoietic failure often observed in patients with AIDS. Soluble TNF receptors (sTNFR) compete for TNF‐&agr; with cell surface receptors and thus may block its activity. The effect of the p55 sTNFR (recombinant TNF‐binding protein‐1 [rTBP‐1]) on the clonogenic growth of hematopoietic progenitor cells from 27 HIV‐infected patients was evaluated in comparison with 11 normal study subjects. Peripheral bloodderived, myelopoietic (i.e., granulomonocytic colony‐forming cells [GM‐CFC]) and erythropoietic (i.e, burst‐forming unit, erythroid [BFU‐E]) colonies were grown in 10‐day semisolid cultures with increasing concentrations of rTBP‐1. Significantly, dose‐dependent increases occurred in GM‐CFC from 17 of 21 AIDS patients and 12 of 21 in BFU‐E at rTBP‐1 concentrations of 1&mgr;/ml to 25 &mgr;/ml. In contrast, rTBP‐1 failed to induce any appreciably increased colony formation in normal cell cultures. In 6 patients treated with highly active antiretroviral treatment (HAART), TBP‐1 alone did not demonstrate the in vitro hematopoiesis‐enhancing effect. This study may provide an initial step in development of therapeutic use of TBP as a TNF‐&agr; antagonist in HIV‐infected patients who do not benefit sufficiently from antiretroviral treatment, and in other conditions in which increased levels of TNF‐&agr; may contribute to hematopoietic deficiencies.

Immune impairments and antibodies to HTLVIII/LAV in asymptomatic male homosexuals in Israel: relevance to the risk of acquired immune deficiency syndrome (AIDS).

We have studied 288 Israeli asymptomatic male homosexuals (MHS) to determine the prevalence of antibodies to HTLVI and HTLVIII and their correlation with impairments of the immune system and serum interferon (IFN). Seropositivity for HTLVI, HTLVIII, or both was found in 1.4, 8.3, and 0%, respectively. Significant decreases in the total peripheral T cells, TH cells, and TH/TS ratio as well as elevated αIFN serum levels were found in the MHS group in comparison with normal controls. Although no difference in the prevalence of either immune derangements or elevated serum IFN was observed between HTLVIII/LAV-seropositive and HTLVIII/LAV-seronegative MHS, the decreases in total T cells, TH cells, and TH/TS ratios were significantly greater in the seropositive MHS. These results indicate that (a) immune impairments and IFN system activation occur commonly in homosexuals, precede their exposure to HTLVIII/LAV, and probably reflect this groups increased risk for AIDS and (b) HTLVIII/LAV infection of MHS aggravates further their preexisting immune impairments.

Thymic Hormones in Viral Infections and Aids

Thymic hormones participate in T-cell differentiation in all three lymphoid cell compartments: bone marrow, thymus gland, and peripheral lymphatic system. These hormones play an essential role in the stepwise process of differentiation and maturation of thymocytes and of T-cells in the absence of antigenic stimulation, thus contributing to a balance between subsets of T-helper, T-cytotoxic and T-suppressor cells (1). Viruses, on the other hand, may cause a disarrangement of the lymphoreticular system, the seriousness of which depends on the aggressiveness of the virus involved. Indeed, following infections such as measles, rubella, cytomegalovirus and dengue, the respective viruses have been detected in peripheral circulating lymphocytes (2). During the course of the infection, viruses may destroy lymphoid cells directly or may persist in the lymphoreticular system leading to the alteration of cellular immune functions. These observations, taken together, led us to formulate the hypothesis that thymic hormones may represent a valuable tool in the therapy against a variety of pathogenic viruses. Without aiming at an exhaustive review of this subject, we present our experience with thymic humoral factor (THF) and most of that obtained by now with other thymic hormone preparations, in the struggle against viral infection in humans.