Simian immunodeficiency virus (SIV) belongs to the family Retroviridae (subfamily Lentivirinae) and is closely related to human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), the etiologic agents of acquired immunodeficiency syndrome (AIDS). Although no reports of infection in humans have been documented, the expanding use of SIV as a model of HIV infection has raised concern about the potential risk of SIV transmission to humans. Therefore, a working group was established by CDC and the National Institutes of Health (NIH) to formulate specific guidelines intended to minimize the risk of SIV transmission to humans. BACKGROUND

Originally reported in 1985, the first isolate from a rhesus macaque was called simian T-lymphotropic virus III (STLV-III) (1). Viral isolates have since been obtained from several species of nonhuman primates including African green monkeys (2), sooty mangabeys (3), pig-tailed macaques (4), and stump-tailed macaques (5). Limited studies of wild-caught African green monkeys from Central Africa indicate a seroprevalence of approximately 30%-50%, apparently without associated immunodeficiency disease. The seroprevalence of SIV among rhesus monkeys in captive colonies (whether from natural infections or interspecies transmission) appears to be low (i.e., 0-1%) (6). In contrast, captive sooty mangabeys may have seroprevalence rates as high as 80% (H. McClure, personal communication). The prevalence of SIV infection among many other nonhuman primate species is unknown.

In rhesus monkeys and other susceptible nonhuman primate species (e.g. pig-tailed macaque, crab-eating macaque), SIV infection leads to a chronic wasting disease syndrome with depletion of CD4 (T4) lymphocytes and lymphadenopathy. The clinical course of this infection in monkeys, like that of AIDS in humans, is complicated by various opportunistic infections (7). SIV also causes a primary encephalopathy with many of the features of HIV-associated encephalopathy (8). Therefore, SIV infection is an important animal model of AIDS. SIV proteins, especially the viral core proteins (i.e., p24, capsid protein), are antigenically related to HIV-I proteins (9). Some SIV isolates, however, are antigenically more related to HIV-2 than to HIV-I by cross-reactivity of viral capsid and envelope proteins. SIV isolates that have been molecularly cloned share approxi-mately 75% of their genomic sequences with HIV-II and approximately 30% with NIV-I (10). SIV isolates are clearly distinct from Type D primate retrovirus (i.e., simian retrovirus

1. that also causes a form of chronic wasting immunodeficiency disease in several primate species (ll). Also, SIV is distinct from simian T-cell lymphotropic virus type I (STLY-I) which shares extensive genomic sequences with human T-lymphotropic virus type I and is associated with T-cell lymphomas in nonhuman primates (12).

SIV can be isolated from a variety of tissues and body fluids-including blood, plasma, cerebrospinal fluid, and parenchyma tissues-of infected nonhuman' primates. Limited data exist concerning the presence or concentration of virus in semen, cervical secretions, saliva, urine, breast milk, and amniotic fluids of experimentally or naturally infected nonhuman primates. However, the virus apparently is rarely isolated from semen, urine, and saliva despite repeated attempts at isolation (M. Daniel, N. Lerche, personal communication). There is no evidence to indicate that SIV is transmitted by the respiratory route (N. Lerche, H. McClure, M. Daniel, personal communication).

The cell tropism of SIV in culture depends partially on the strain of virus propagated and conditions of cell culture. Strains of SIV have been successfully cultured in human lymphocyte cell lines (e.g., HuT 78, HT, CEMx174) and in primary human and nonhuman primate peripheral blood leukocyte cultures (13). SIV appears to be primarily tropic for CD4 (T4)-positive leukocytes and has not been successfully propagated in B-lymphocyte cell lines (e.g., Raji). SIV antigen has been demonstrated by immunohistochemical methods in lymph node sinus histiocytes, macrophages, and giant cells (14) as well as in macrophage-derived cells in brain tissue from diseased monkeys (8).

Limited data exist concerning the reactivation of Herpesvirus simiae (B virus) or other latent infectious agents in SIV infected macaque monkeys. However, all macaque monkeys not proven to be free of B virus infection, regardless of SIV infection status, should be regarded as infected with B virus and handled according to published guidelines (15). The routine screening of macaques for evidence of B virus infection or SIV infection is not recommended. However, in situations in which studies may cause immunosuppression (e.g., during experimental SIV infections), the investigator may elect to determine the infection status of the animals because a virus shedding may be enhanced in infected animals.

EVALUATING THE RISK OF SIV TRANSMISSlON TO HUMANS

The risk, if any, of human infection with SIV has not been defined. However, since SIV shares many characteristics with HIV, many of the same biosafety precautions are 700 indicated. No serologic or virolcgic evidence of infection in humans exists; specific precautions in handling SIV are based on recommendations developed for HIV and other lentiviruses. No licensed tests exist for serologic evaluation of humans exposed to SIV. The absence of licensed tests complicates medical surveillance and investigations of the virus infection following exposure to SIV. In addition, the antigenic cross-reactivity between SIV and HIV may complicate testing of exposed humans. However, standardized serologic procedures that test for SIV antibody are used in laboratories performing research with the virus. Recently, a protein unique to SIV and HIV-2 (product of gene vpx) was used as antigen in a serologic test that may allow easier distinction between HIV-I and SIV antibodies (16). Furthermore, gene ampli-fication (i.e., polymerase chain reaction) may allow differentiation of specific virus gene sequences directly from specimens obtained from exposed persons. Based on these events, development of specific and sensitive tests is under way.

GUIDELINES TO PREVENT SIV INFECTION IN LABORATORY WORKERS AND ANIMAL HANDLERS Exposure Concerns. In the laboratory, SIV must be presumed to be present in all SIV cultures, in all materials derived from such cultures, in all specimens from SIV antibody-positive nonhuman primates, and in/on all equipment and devices coming in contact with these materials. In this setting, the skin (especially when scratches, cuts, abrasions, dermatitis, or other lesions are present) and mucous membranes of the eye, nose, and mouth should be considered as potential pathways for virus entry; contact of these sites with SIV-containing materials should be considered an expo-sure to SIV.

Biosafery Levels. Biosafety level (BSL) 2 standards and special practices, containment equipment, and facilities, as described in the CDC/NIH publication Biosafery in Microbiological and Biomedical Laboratories (17), are recommended for activities involving all clinical specimens, body fluids, and tissues from SlY-infected primates, In laboratories maintaining BSL 2, personnel must have documented specific training in handling primate retroviruses, and the laboratory must have limited and properly secured access and written standard operating procedures for techniques in which SlY is used. Procedures involving cultures of SlY should be conducted in biological safety cabinets or other physical containment equipment. Inoculation Precautions. In the research laboratory, inoculation of SIV-containing material represents an important potential route of exposure to SIV in humans. The use of syringes, needles, glass, and other sharp objects should be avoided, but when their use is essential, needles and disposable cutting instruments should be discarded after use into a lidded puncture-resistant container located in the work area. Needles should not be resheathed, bent, broken, removed, or otherwise manipulated by hand.

Gloves. Latex or vinyl gloves should be worn by all personnel engaged in activities that may involve direct skin contact with infectious specimens, cultures, or tissues. Gloves should not be washed or disinfected for reuse; reuse of such gloves may cause "wicking" (i.e., enhanced penetration of liquids through undetected holes in the glove) or deterioration of the gloves. When gloves have become visibly contaminated, they should be carefully removed and, after the hands are washed, replaced with a fresh pair of gloves. Handwashing with soap and water immediately after infectious materials are handled and work is completed, even when gloves have been worn, should be routine practice.

Clothing. Laboratory coats, gowns, or uniforms should be worn by laboratory workers when engaged in any work involving SlY or materials known or suspected to contain SIV. Clothing that becomes contaminated with SIV or SIV-containing materials should be decontaminated before being laundered or discarded. Clothing can be decontaminated by extensive soaking of the garment with chemical disinfectants (e.g., 1 to 10 dilution of household beach).

Aerosol Control. Although aerosol transmission of SIV has not been demonstrated, the generation of aerosols, droplets, splashes, and spills should be avoided. A biological safety cabinet should be used for all procedures that might generate aerosols or droplets and for all infected cell culture manipulations. When centrifuging infected materials, centrifuge containers with safety caps that are designed to contain aerosols (in the event of spillage) should be used. When cell sorters are used, plastic shielding or other containment devices should be used to reduce exposure to infectious droplets. Contaminated Virus Preparations. During the propagation of SIV in the research laboratory, manipulation of concentrated virus preparations or conduct of procedures that may produce aerosols or droplets should be performed in a BSL 2 facility, with additional practices and containment equipment recommended for BSL 3 (17). These practices should include wearing closed-front surgical-type gowns, masks and protective eyewear or face shields, and latex or vinyl gloves that extend to cover the wrist and sleeves of the surgical gown. Activities involving large-volume production or manipulation of highly concentrated SIV should be conducted in a BSL 3 facility, using only BSL 3 practices and equipment. All discarded cultures and laboratory supplies used in experimental manipulations of cultures should be autoclaved before disposal.

Decontamination. The susceptibility of SIV to chemical disinfectants has not been defined. Work surfaces, however, should be decontaminated daily with commercially available chemical disinfectants such as sodium hypochlorite solution 10% (1 to 10 dilution of household beach), ethanol 70%-85%, or ethanol-iodine complex 2%. These effectively inactivate HIV-I (18,19). Prompt decontamination of spills (immediate absorption and control of the spill and soaking of the contaminated area with chemical disinfectant) should be standard practice. Gloves should be worn when cleaning up such spills. The use of plastic-backed absorbent padding to control spillage during manipulation of cultures or other SIV-containing fluids should be encouraged.

Animal Biosafety Levels. Animal BSL 2 practices, containment equipment, and facilities are recommended for activities involving nonhuman primates or any animals experimentally infected or inoculated with SIV. Animal-care personnel, investigators, technical staff, and other persons who enter animal rooms should wear coats, protective gloves, coveralls or uniforms, and, as appropriate, face shields or surgical masks and eye shields to protect the skin and mucous membranes of the eyes, nose, and mouth.

Handling SIV-Infected Nonhuman Prlmates. Nonhuman primates experimentally infected with SlY may have other primary, as well as opportunistic, pathogens in their body fluids and tissues. Thus, laboratory workers and animal handlers should follow accepted BSL 2 practices at all times to prevent inadvertent exposure to agents that may be present in clinical specimens or body fluids. All macaque monkeys not known to be free of Herpesvirus simiae (B virus) should be regarded as infected and handled according to published guidelines (15).

Personnel Training. Primary investigators, other scientific personnel and other persons who handle nonhuman primates used in SIV research should be trained in proper methods of animal restraint and use of protective clothing. Animal handlers should be familiar with various drugs routinely used for providing chemical restraint and with proper procedures for administering medications. All persons engaged in research involving nonhuman primates should be specifically trained in the natural history of SIV infection. Particular attention should be given to the need to wear protective clothing to prevent mucous membrane contact with potentially infectious material, particularly animal blood from an SIV-infected nonhuman primate. Caution should be emphasized during venipuncture procedures or the administration of injections to nonhuman primates involved in SIV research. lntravenous injections of nonhuman primates should be done while the animal is anesthetized and should be administered through a plastic or teflon catheter with syringes fitted with interlocking connectors.

Medical Surveillance. A licensed test specific for SIV antibody is not yet available. Standardized serologic procedures to identify SIV antibody are used in laboratories performing research with the virus. A medical surveillance program should be in place in all laboratories that test specimens, conduct research, or produce reagents involving SIV. The nature and scope of the surveillance program will vary by institutional policy and applicable local, state, and federal regulations (20). Laboratories performing research with SIV should initiate a program to store serum from laboratory workers. Serum specimens should be collected at 6-month intervals and stored. Routine testing of the serum is optional but, if performed, should be done using standardized serologic procedures in qualified laboratories. Human Exposure to SIV, if a laboratory worker has a parenteral, skin, or mucous membrane exposure to blood, body fluids, or virus culture material from nonhuman primates, the source material should be identified and, if possible, tested for the presence of SlY. All wounds incurred from SIV-infected nonhuman primates or from SIV-contaminated instruments should be cleansed with soap and water. Such incidents should be reported to the animal-care supervisor and/or laboratory supervisor and recorded in an accident report log. If the source material is positive for SIV antibody, virus, or antigen or unavailable for examination, the worker should be counseled regarding the risk of infection and evaluated medically. The worker should be advised to report and to seek medical evaluation for any acute febrile illness that occurs within 12 weeks after the exposure. Medical evaluation should include examination for serum antibody against SlY. Seronegative workers should be retested 6 weeks after the exposure and periodically thereafter (e.g., 12 weeks and 6 months after exposure). All institutions should establish written policies regarding the management of laboratory exposure to SIV; such policies should deal with confidentiality, counseling, and other related issues. The lack of data concerning the potential transmission of SIV between humans does not allow for specific recom-mendations concerning behavior changes in a person confirmed seropositive for SIV. However, an HIV-seropositive person should not donate blood.

Postexposure Treatment. No effective prophylactic treatment for SIV exists; research is needed in animals concerning postexposure prophylaxis (e.g., immune globulin, antiviral therapy). Data from such research may be useful in future exposures of humans to SIV.

The working group consists of MD Lairmore, DVM, PhD, JE Kaplan, MD, Div of Viral Diseases, M Rayfield, PhD, AIDS Laboratory, AIDS Program, B Brown, DVM, Office of Scientific Svcs, Center for Infectious Diseases; JW McVicar, DVM, MS, Office of Biosafety, Office of the Director, CDC. MD Daniel, DVM, PhD New England Regional Primate Center, Harvard Medical School, Southborough, Massachusetts. NW Lerche, DVM, MPVM, California Regional Primate Research Center. Univ of California, Davis. PL Nara, DVM, PnD National Cancer Institute. HM McClure, DVM, Yerkes Regional Primate Research Center, Emory Univ, Atlanta, Georgia. RW McKinney, PhD, Office of Biosalety, DO Johnsen, DVM, Div of Research Resources, R Purcell, MD, National Institute ofAllergy and Infectious Diseases; CJ Gibbs Jr, PhD, National Institute of Neurological Disorders and Stroke, National Institutes of Health. M Hendry, DVM, DSci, Div of Virology, Food and Drug Administration. P Gerone, DVM, Delta Regional Primate Research Center, Tulane Univ, Covington, Louisiana. J Allan, DVM, Southwest Foundation for Biomedical Research, San Antonio, Texas. JL Ribas, DVM, Dept of Virus Diseases, Walter Reed Army Institute of Research, Washington, DC. HJ Klein, VMD, DS, Laboratory Animal Resources, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania. PB Jahrling, PhD, Dept of Pathogenesis and lmmunology, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland.

References

1. Daniel MD, Letvin NL, King NW, et al. Isolation at T-cell tropic HTLY-III-like retrovirus from macaques. Science 1985;228:1201-4.

2. Ohta Y, Masuda T, Tsujimoto H, et al. Isolation of simian immunodeficiency virus from African green monkeys and seroepidemiologic survey of the virus in various nonhuman primates. Int J Cancer 1988;411 115-22.

3. Fultz PN, McClure HM, Anderson DC, Swenson RB, Anand R, Srinivasan A. Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebusatys). Proc Nat Acad Sc USA 1986;83:5286-90.

4. Benveniste RE, Arthur LO, Tsai C-C, et al. Isolation of a lentivirus from a macaque with lymphoma: comparison with NTLY-III/LAV and other lentiviruses. J Virol 1986;60:483-90

5. Lowenstine LJ, Lerche NW, Marx P, Pederson NC, Jennings M, Gardner MS. Update on simian imrnunosuppressive retrovirus (SIV) studies at the California Primate Research Center (CPRC). Presented at the Symposium on Nonhuman Primate Models for the Acquired Immunodeficiency Syndrome (AIDS), Atlanta, Georgia, October 8-10, 1987.

6. Daniel MD, Letvin NL, Sehgal PK, et al. Prevalence of antibodies to three retroviruses in a captive colony of macaque monkeys. Int J Cancer 1988;41:601-8.

7. King NW. Simian models of acquired immunodeficiency syndrome (AIDS): a review. Vet Pathol 1986;23:345-53.

8. Ringler DJ, Hunt RD, Desrosiers RC, Daniel MD, Chalifoux LV, King NW. Simian immunodeficiency virus-induced meningoencephalitis; natural history and retrospective study. Ann Neural 1988;23(suppl):S101-7.

9. Kanki PJ, McLane MF, King NW Jr, et al. Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLY-lll. Science 1985;228:1199-201. 10.Chakrabarti L, Guyader M, Alizon M, et al. Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses. Nature 1987;328:543-7. 11.Heidecker G, Lerche NW, Lowenstine LJ, et al. Induction of simian acquired immunedeficiency syndrome (SAIDS) with a molecular cone of a type D SAlDS retrovirue. J Virol 1987;61:3066-71. 12.Watanabe T, Seiki M, Tsujimoto H, Miyoshi Hayami M, Yoshida M. Sequence homology of the simian retrovirus genome with human T-cell leukemia virus type I. Virology 1985;144:59-65.

10. Kannagi M, Yetz JM, Letvin NL. In vitro growth characteristics of simian T-lymphotropic virus type Proc Nat Acad Sci USA 1985;82:7053-7. 14.Ward JM, O'Leary TJ, Baskin GB, et al. Immunohistochemical localization of human and simian immunodeficiency viral antigens in fixed tissue sections. Am J Pathol 1987;127:199-205. 15.CDC. Guidelines for prevention of Her esvirus simtae (B virus) infection in monkey handlers. MMWR 1987;36:680-2,687-9.

11. Henderson LE, Sowder RC, Copeland TD, Benveniste RE, Oroszlan S. Isolation and characterization of a novel protein (X-ORF product) from SIV and HIV-2. Science 1988;241:199-201.

12. CDC, National Institutes of Health. Biosafety in microbiologicai and biomedical laboratories. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, 1984; DHHS publication no. (CDC)84-8395.

13. Martin LS, McDougal JS, Loskoski SL. Disinfection and inactivation of the human Tlymphotropic virus type III/lymphadenopathy-associated virus. J Infect Dis 1985,152:400-3

14. Resnick L, Veren K, Salahuddin SZ, Tondreau S, Markham PD. Stability and inactivation of HTLV-III/LAV under clinical and laboratory environments. JAMA 1986:255:1887-91.

15. US Department of Labor, US Department of Department of Health and Human Services. Joint advisory notice: HBV/HIV. Federal Register 1987;52(21O):41818-24.

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