FERTILITY AND STERILITY Copyright C> 1992 The American Fertility Society

Vol. 58, No.4, October 1992

Printed on acid-free paper in U.S.A.

Semen transmission of human immunodeficiency virus

Ann A. Kiessling, Ph.D. Associate Clinical Professor Surgery

Director Reproductive Biology, Faulkner Centre for Reproductive Medicine, Boston, Massachusetts

Received July 18, 1992. Reprint requests: Ann A. Kiessling, Ph.D., Faulkner Centre for Reproductive Medicine, 1153 Centre Street, Boston, Massachusetts 02130. The opinions and commentary expressed in this non-peer-reviewed article are solely those of the author. Its publication does not imply endorsement by the Editor or The American Fertility Society. Vol. 58, No.4, October 1992

The epidemiology of the outbreaks of opportunistic infections (1) suggested that semen transmitted acquired immune deficiency syndrome (AIDS) as early as 1981, before human immunodeficiency virus (HIV) was identified as the etiologic agent. Direct evidence for HIV in semen appeared in 1984, when two groups (2, 3) reported the recovery of virus-infected mononuclear cells from semen. One group detected virus infected cells in two homosexual patients with AIDS (2) and the other in a seropositive, but asymptomatic, homosexual (3). Shortly thereafter, we reported evidence of unexpectedly high concentrations (on the order of 107 to 108 particlesfmL) of cell-free HIV in seminal fluids from three homosexual patients with AIDS: one with Kaposi's sarcoma, one patient with AIDS related complex, and one asymptomatic homosexual patient (4, 5). Thus, it became clear that HIV was present in semen as cell-free as well as cell-associated virus. None of these early studies reported seropositive patients free of semen virus. The next pressing questions to be answered were how did the virus get into semen and would treatment or course of disease affect its presence? These issues are central to understanding the role of the male reproductive tract in the course and transmission of AIDS. Such considerations not only affect the design of treatment modalities for HIV positive patients but also impact areas of reproductive concern. For example, could semen be infectious before seroconversion? Current sperm banking procedures and counsel to couples at high risk for HIV infection rely on the notion that seroconversion would preceed the production of infectious semen. Although a likely scenario for patients infected intravenously, direct evidence is lacking and the risks may be different for patients infected venereally. A second example relates to reproductive concerns of HIV positive patients: do some men never shed virus into semen? Is it possible to recover HIV-free sperm from ejaculated semen or from epididymal aspirations? These questions have been raised before (6, 7) and pressures to answer them will continue to mount as the population of reproductive age HIV -positive individuals increases and improved treatment regimen prolong life expectancy. For these reasons, it seems important for reproductive health professionals to fully understand current knowledge about HIV in semen, particularly in light of recent, conflicting reports. Semen HIV could derive solely from infected leukocytes in the reproductive tract. If this were the case, ejaculates containing cell-free virus would also contain infected leukocytes. It will be important to discover leukocyte traffic patterns that lead to infected ejaculates. Kiessling

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However, studies of male mice (8, 9) suggest that other reproductive tract host cells, such as epididymal epithelium, could support virus replication and contribute to the virus load in semen. In this circumstance, cell-free virus could be ejaculated in the absence of infected white cells. More recent studies have provided information on these possibilities, although they were not directly aimed at answering these questions, but the results vary widely in the detection of HIV infection in semen. Early in 1991, Kreiger et al. (10) studied peripheral blood cells (PBCs) and semen from 34 seropositive men, mostly homosexuals, 20 of whom had AIDS. Their assay was detection of released viral antigen (p24) after coculture with target host cells for up to 28 days. Human immunodeficiency virus was detected in PBCs from all subjects and from serum in 88% of subjects. Sixteen (29%) of the 55 semen specimens from 11 (32%) of the subjects were positive. The positive samples were distributed equally between the AIDS and the asymptomatic patients, and although men with HIV -positive semen tended to have lower CD4+ peripheral lymphocyte counts (100 ± 140 cells/ML) than those with HIV-negative semen (210 ± 160 cells/ML), the differences were not statistically significant. There was also no significant difference with zidovudine therapy. Interestingly, three of the 16 samples were HIV positive in the cell-free seminal plasma fraction only, suggesting the negative semen mononuclear cells were not the source of the virus. At approximately the same time, Van Voorhees et al. (11) reported a comparison study of HIV detection by infectivity assay and the technique of HIV DNA amplification by polymerase chain reaction (PCR). Semen and blood samples from 25 seropositive symptomatic homosexuals were evaluated. In their infectivity assay, virus was not recovered from PBCs of all the subjects (19 [74%] of 24), and only 4 (16%) of the 25 semen samples were positive for HIV. Interestingly, two of the positive semen samples had infectious virus in seminal plasma only. However, although more (23) of the blood cell samples were positive for HIV by PCR analysi~, they only detected one positive semen sample by this technique. In contrast, in the fall of 1991, Mermin et al. (12) studied the incidence of HIV in blood and semen from 23 HIV -infected men (risk factors not stated) by PCR. Peripheral blood cells were positive for HIV in all men and 19 (87%) of semen samples. Using reverse transcription of viral ribonucleic acid into 668

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deoxyribonucleic acid before PCR amplification, 15 (65%) of cell-free seminal fluid samples were determined positive for free virus, 3 (16%) of which were negative for HIV in the cell fraction. These results of increased sensitivity of HIV detection by PCR agree with several studies comparing PCR with infectivity assays (13, 14). A more recent report by Anderson et al. (15) of semen HIV detection in a larger patient cohort using a "microculture technique" revealed an even lower incidence of positive semen in a cohort of seropositive, mostly symptomatic homosexuals: 9 (9%) of 95. The reason for this surprisingly low incidence is unclear, but the low numbers of positive men make interpretation of risk factors for infected semen difficult to predict. However, as was the case with the earlier report from this laboratory (11), five (55%) of the infectious samples had virus only in the cell-free seminal plasma. In summary, these reports confirm the earlier findings that HIV is present in the semen of infected males. Assayed by virus infectivity, 30%, 16%, and 9% of semen samples were positive for HIV (references 10, 11, and 15, respectively). Assayed by PCR, 87% and 4% of samples were virus positive (references 12 and 11, respectively). This wide range in semen virus detection undoubtedly reflects assay techniques as well as variations in patient population. Although none of the study designs specifically addressed the problem of the source of virus, it is noteworthy that all methods identified some samples that contained cell-free virus in the absence of detectable virus in semen cells. The incidence of cellfree virus varied from 5% to 13% of samples: 3 of 55 (10), 2 of 25 (11), 3 of 23 (12), and 5 of 95 (15). Interestingly, none of 13 positive samples detected in the 120 ejaculates studied in one laboratory (11, 15) were reported to contain both cell-free and cellassociated HIV: 6 were positive only in the cell pellet and 7 only in the filtered semen sample. These results suggest that in this patient population, either the sensitivity of the assay restricts detection of positive samples to only those with very high levels of infection, or two types of semen infection exist, one associated with ejaculated white cells and the other deriving from another source of virus. This is a notion in need of investigation. In contrast, the PCR study detected cell-free virus in 75% of the positive semen cell samples. This suggests that cell-free HIV may become inactivated during the manipulations necessary to collect and prepare the semen samples for cell culture, a notion Fertility and Sterility

certainly in keeping with known fragilities of membrane viruses such as HIV. Taken together, these findings suggest that the reported incidence of HIV in semen is more dependent on the technique used than on the patient population. In experienced laboratories, peR appears to be a much more rapid and sensitive tool for detecting HIV in semen than virus culture. Moreover, although many discussions have appeared about the possible role of infected leukocytes in semen transmission of HIV, there has yet to appear an explanation of the appearance of cell-free virus in the absence of infectious semen cells, despite the fact that this circumstance accounted for half of all positive semen samples in two reports from one research team. Thus, at this time, the relationships between risk factors, disease status and treatment modalities to the production of infected semen are unclear and in urgent need of careful study. Key Words: Semen, human immunodeficiency VIruS.

REFERENCES 1. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, et a1. Pneumocystis Carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Eng J Med 1981;305:1425-30. 2. Zagury D, Bernard J, Leibowitch J, Safai B, Groopman JE, Feldman M, et a1. HTLV-III in cells cultured from semen of two patients with AIDS. Science 1984;226:449-51. 3. Ho DD, Schooley RT, Rota TR, Kaplan JC, Flynn T, Salahuddin SZ, et a1. HTLV-III in the semen and blood of a healthy homosexual man. Science 1984;226:451-3. 4. Borzy MS, Kiessling AA. Reverse transcriptase activity in seminal fluids from patients with AIDS. Proceedings of the International Conference on Acquired Immunodeficiency Syndrome, Atlanta, Georgia, 1985.

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5. Borzy MS, Connell RS, Kiessling AA. Detection of human immunodeficiency virus in cell-free seminal fluid. J Acquir Immune Defic Syndr 1988;1:419-24. 6. Kiessling AA. Retroviruses and reproduction. Fertil Steril 1989;51:756-8. 7. Kiessling AA. The role of assisted reproductive technologies in yielding HIV-free offspring of HIV-infected parents. In: Melica F, editor. AIDS and human reproduction. Basel, Switzerland: S. Karger, 1991:139-44. 8. Kiessling AA, Crowell RC, Fox C. Epididymis is a principal site of retrovirus expression in the mouse. Proc Natl Acad Sci USA 1989;84:8667-71. 9. Panthier J-J, Gounon P, Condamine H, Jacob F. Pattern of expression of ecotropic murine leukemia virus in gonads of inoculated SWR/J mice. J Virol 1989;63:2134-42. 10. Kreiger IN, Coombs RW, Collier AC, Ross SO, Chaloupka K, Cummings DK, et a1. Recovery of human immunodeficiency virus type I from semen: minimal impact of stage of infection and current antiviral chemotherapy. J Infect Dis 1991;163:386-8. 11. VanVoorhis BJ, Martinez A, Mayer K, Anderson DJ. Detection of human immunodeficiency virus type 1 in semen from seropositive men using culture and polymerase chain reaction deoxyribonucleic acid amplification techniques. Fertil Steril 1991;55:588-94. 12. Mermin JH, Holodniy M, Katzenstein DA, Merigan TC. Detection of human immunodeficiency virus DNA and RNA in semen by the polymerase chain reaction. J Infect Dis 1991;164:769-72. 13. Edwards JR, Ulrich PP, Weintrub PS, Cowan MJ, Levy JA, Wara DW, et a1. Polymerase chain reaction compared with concurrent viral cultures for rapid identification of human immunodeficiency virus infection among high-risk infants and children. J Pediatr 1989;115:200-3. 14. Rogers MF, Ou C-Y, Rayfield M, Thomas PA, Schoenbaum EE, Abrams E, et a1. Use of the polymerase chain reaction for early detection of the proviral sequences of HIV in infants born to seropositive mothers. New Engl J Med 1989;320:164954. 15. Anderson DJ, O'Brien TR, Politch JA, Martinez A, Seage GR, Padian N, et a1. Effects of disease stage and zidovudine therapy on the detection of human immunodeficiency virus type 1 in semen. JAMA 1992;267:2769-74.

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Semen transmission of human immunodeficiency virus.

FERTILITY AND STERILITY Copyright C> 1992 The American Fertility Society Vol. 58, No.4, October 1992 Printed on acid-free paper in U.S.A. Semen tra...
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