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Previous Volume 330:172-177 January 20, 1994 Number 3 Next

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Simian immunodeficiency viruses (SIVs) are primate lentiviruses that are morphologically similar and biologically related to human immunodeficiency viruses (HIVs)^1,2,3,4. SIVs naturally infect some nonhuman primate species, such as African green monkeys and sooty mangabey monkeys, without causing immunodeficiency. In contrast, experimental SIV infection of other susceptible primate species, such as macaques, can cause chronic wasting syndromes and a disease similar to the human acquired immunodeficiency syndrome (AIDS)^5,6,7,8,9,10. Because of the similarities between the human and nonhuman lentiviruses, SIV and its susceptible primate host have become the principal model for studying the pathogenesis of AIDS and developing an HIV vaccine. The SIVs from mangabeys and captive macaques (SIV_MAC) are genetically and antigenically related most closely to HIV type 2 (HIV-2), with substantial serologic cross-reactivity¹¹. Recent molecular evidence suggests that HIV-2 and SIV_MAC may be even more closely related to each other than was previously thought^12,13. However, infection of a human with SIV has not been documented.

We recently described a laboratory worker in whom antibodies cross-reactive to HIV-2 and SIV developed after percutaneous exposure to blood from a macaque experimentally infected with SIV¹⁴. SIV was never detected by sensitive molecular and virologic tests, and antibodies to HIV-2 and SIV decreased steadily over the next two years, suggesting that this person did not become persistently infected with SIV. The appearance of this first case led us to test 60 serum samples in April 1992 that had been collected from workers in two SIV research facilities. We found a second researcher in a different U.S. laboratory who had antibodies to HIV-2 and SIV. We present evidence from the investigation of this second case that confirms SIV infection of a human, and we report the isolation of SIV from a human (SIV_HU).

Methods

The researcher was interviewed in April 1992. Twenty serum samples collected between September 1988 and December 1992 were tested for antibodies to HIV type 1 (HIV-1) by an HIV-1-peptide enzyme-linked immunosorbent assay (ELISA) (IAF Biochem International, Montreal) and for antibodies to HIV-2 and SIV. Testing for HIV-2 and SIV included a synthetic-peptide ELISA and Western blotting for HIV-2 (Cambridge Biotech, Rockville, Md.). For the ELISA, a peptide from the immunodominant area of the transmembrane protein of HIV-2 was used (envelope amino acids 589 to 605). This peptide ELISA is very sensitive because of the high concentration of immunodominant epitopes on microwells, as opposed to the lower concentrations in ELISAs based on viral lysates, and is very useful in detecting early seroconversion¹⁴.

Each month from May 1992 to May 1993, 60 ml of blood was obtained from the researcher and treated with heparin, and the peripheral-blood mononuclear cells (PBMCs) were separated by Ficoll-Hypaque centrifugation and cultured. Unfractionated PBMCs and PBMCs depleted of CD8+ cells were also cultured. For the depletion of CD8+ cells, CD4+ T cells were purified by negative selection with anti-CD8+-coated magnetic beads according to the manufacturer's instructions (Dynal, Great Neck, N.Y.). PBMCs and purified CD4+ T cells were then cultured in RPMI-1640 (GIBCO, Grand Island, N.Y.) medium containing 10 percent fetal-calf serum and 1 percent antibiotics and stimulated with phytohemagglutinin for three days. The cells were subsequently cultured alone or with normal phytohemagglutinin-activated human or rhesus PBMCs in the presence of 10 percent purified interleukin-2. Culture supernatants were removed every three to four days and analyzed for the presence of reverse transcriptase activity dependent on magnesium (20 mM), according to a modification of the method of Willey et al.,¹⁵ and for SIV p27 gag antigen (Coulter, Hialeah, Fla.).

A long-terminal-repeat fragment (127 to 167 base pairs [bp]) of proviral DNA was amplified from cultured cells infected with SIV and HIV-2. The polymerase chain reaction (PCR) amplification was performed under conditions previously described¹⁴ with SIV and HIV-2 consensus primers (positions 300 to 328 and 402 to 427, respectively, based on an analysis of SIV_SMMH4). Duplicate samples of the amplified product underwent electrophoresis followed by hybridization with Southern blotting to two internal probes end-labeled with ³²P.

The first blot was hybridized with SIV and HIV-2 probes located at the 5' end of the deletion sequence characteristic of SIV isolates (position 354 to 373, on the basis of the sequence of SIV_SMMH4, and position 356 to 376, on the basis of the sequence of HIV-2_BEN). The second blot was hybridized with a probe specific for HIV-2 (position 380 to 410, on the basis of the sequence of HIV-2_BEN) derived from the sequence of 40 to 44 bp that is absent in viral isolates of SIV_SMM and SIV_MAC^13,16,17.

An env fragment was amplified with primers designed from HIV-2 and SIV_SMM and SIV_MAC consensus sequences that encompass the V1 region and half of the V2 region. This fragment shows a high level of interstrain and intrastrain sequence variability, as previously reported¹⁶ (the positions of primer pairs used were 6857 to 6884 and 7135 to 7164 and were based on the sequence of SIV_MAC251). The amplified product was then sequenced, and the sequence was compared with that of other SIV isolates. To facilitate cloning and sequencing of the envelope product, 2 microl of the primary amplification sample was subjected to nested PCR, with internal primers (positions 6885 to 6908 and 7135 to 7164, based on an analysis of SIV_MAC251). The product was cloned into pT7 blue vector (Novagen, Madison, Wis.) according to the manufacturer's instructions. Double-stranded plasmid DNA was subsequently sequenced by the dideoxy chain-termination method with a Sequenase version 2.0 kit (U.S. Biochemical, Cleveland).

PCR was also done each month from April 1992 to May 1993 on 150,000 to 450,000 uncultured PBMCs with SIV generic env primers and probes, and the process was repeated with SIV_HU-specific env primers and probes under conditions previously described¹⁴. The amplified env fragments obtained in April 1992 and October 1992 were sequenced, and their sequences were compared with those of other SIV isolates as described above.

In August 1992, 10 ml of blood treated with heparin was inoculated within 24 hours of collection into a rhesus monkey and a pigtailed macaque. Blood samples were obtained monthly from the monkeys for the next eight months. Serum samples were tested for antibodies to HIV-2 and SIV, and PBMCs were lysed and examined by PCR for evidence of SIV.

Case Report

The researcher, who had been working with SIV since 1985, had handled clinical specimens from macaques experimentally infected with SIV, performed serologic tests on specimens of macaque blood, and established SIV cultures. In September and October 1989, the researcher had severe dermatitis on the forearms and hands that was treated with oral corticosteroids. The researcher performed serologic tests on clinical specimens from SIV-infected monkeys without wearing gloves and worked with SIV-infected cell cultures, although the worker performed all culture procedures in a laminar airflow biosafety cabinet while wearing a laboratory coat and gloves. The researcher could not recall any episode of direct skin exposure to SIV. The researcher had never traveled outside the Americas and had no identified risk factors for HIV-2 infection, such as having had a sexual partner from West Africa. The researcher had never received a blood transfusion, had never injected drugs, and had been in a mutually monogamous sexual relationship since 1985. When tested in May 1992, the researcher's partner was negative for antibodies to HIV-2 and SIV.

Results

All the researcher's serum samples were negative for antibodies to HIV-1. Although all 11 serum samples obtained from September 1988 to November 1989 were negative for antibodies to HIV-2 and SIV (only 2 of the measurements are shown in Figure 1), all serum samples obtained after April 1990 had antibodies to HIV-2 and SIV on HIV-2-peptide ELISA and on HIV-2 Western blot assay (Figure 1). The results of Western blotting for HIV-2 showed the gradual appearance of antibodies to various viral proteins, characteristic of a seroconversion, and antibody titers increased with time from 1:400 to 1:3200.

View larger version (34K): [in this window] [in a new window]   Figure 1. Results of Serologic Tests for HIV-2 and SIV. Panel A shows the titers of serial serum samples on HIV-2-peptide ELISA. The asterisk indicates the titer corresponding to the blood sample from which SIVHU was isolated, and the dagger the titer corresponding to the blood sample inoculated into two macaques. Panel B shows the results of Western blotting of serial serum samples for HIV-2.

 
One primary culture of CD8+-depleted PBMCs obtained in June 1992 was positive for virus, with SIV p27 gag antigen and reverse transcriptase activity detected after 24 days of culture (Figure 2A). This June 1992 isolate, designated SIV_HU, was successfully passaged and multiplied in normal human PBMCs (Figure 2B).

View larger version (16K): [in this window] [in a new window]   Figure 2. Isolation of Infectious SIV from CD4+ T Cells. Panel A shows the primary isolation of SIVHU from culture supernatants. Unfractionated PBMCs and CD4+ T cells were cultivated alone or with normal human or normal rhesus PBMCs in the presence of interleukin-2. Panel B shows the passage and multiplication (in normal human PBMCs) of SIVHU. The high levels of magnesium-dependent reverse transcriptase activity and high SIV p27 gag antigen levels detected in the culture supernatants were reflective of SIV propagation.

 
Amplification of SIV_HU with long-terminal-repeat primers followed by hybridization with probes specific for SIV and HIV-2 showed SIV_HU to have a deletion of 40 to 44 bp in the long terminal repeat, which is characteristic of SIV isolates and which distinguishes them from HIV-2 isolates (Figure 3)^13,16,17.

View larger version (15K): [in this window] [in a new window]   Figure 3. Identification of an SIVSMM and SIVMAC "Signature" Sequence in SIVHU Constituting a Specific Deletion of 40 to 44 bp in the Long-Terminal-Repeat Region. The region encompassing the sequence was amplified with SIV and HIV-2 consensus primers, and the product was transferred onto two blots. The upper blot was hybridized with SIV and HIV-2 probes located at the 5' end of the deletion sequence characteristic of SIV isolates. The lower blot was hybridized with an HIV-2-specific probe derived from the sequence of 40 to 44 bp that is absent in viral isolates of SIVSMM and SIVMAC. Hut-78 is an uninfected T-cell line.

 
Sequence analysis of an amplified env fragment from SIV_HU further showed it to be most similar (94 percent homology) to a clonal sequence of SIV_B670 and less similar (76.1 to 80.6 percent homology) to other SIV strains, including ones from other sooty mangabeys (Figure 4). The researcher's laboratory primarily worked with SIV_B670, which was originally isolated from a sooty mangabey.

View larger version (61K): [in this window] [in a new window]   Figure 4. Comparative Analysis of the env SIVHU Sequence with Representative SIV and HIV-2 Sequences. Dashes indicate sequence homology, and dots indicate gaps introduced for optimal alignment. The number 1 in the upper left-hand corner corresponds to nucleotide positions 6881, 6910, 7005, 6427, and 6451 in SIVSMMH4, SIVMAC251, HIV-2BEN, HIV-2D194, and HIV-2ROD, respectively. The sequence data on SIVB670 are unpublished. The sequence of SIVE233 (a positive control used in PCR) was determined in our laboratory from uncultured PBMCs from an SIV-infected monkey. The sequences of samples obtained from the patient in April and October 1992 and amplified by PCR were 100 percent identical to the sequence identified in cultured cells from the June 1992 sample (SIVHU) and are therefore not shown.

 
PCR amplification of DNA from uncultured PBMCs showed SIV env sequences in cells obtained in April and October 1992 and in March and May 1993. Analysis of the amplified products from April and October 1992 showed that they were identical to the env fragment amplified from SIV_HU (Figure 4).

Two monkeys inoculated with the researcher's blood remained seronegative for SIV, and the results of PCR were negative.

Discussion

The risk of human infection with SIV is no longer merely hypothetical. We have documented such an infection and have isolated SIV from a person who became infected after exposure to SIV-infected nonhuman primates. Our findings support both the idea that this lentivirus can cause zoonotic infections and the hypothesis that HIV-2 originated from SIV. However, on the basis of this one incident it is difficult to speculate about the evolution and origin of HIV-1 and AIDS. The movement of lentiviruses between nonhuman primates and humans is only beginning to be understood, and infection of humans with SIV_CPZ, a closer counterpart to HIV-1,¹⁸ has not been reported.

The evidence of infection in our subject includes seroconversion, persistent seropositivity after the presumed exposure, increasing antibody titers with identification of seroreactivity to new viral gene products over time, isolation of SIV, and molecular evidence of an identical SIV sequence in DNA amplified at other times. Our molecular data show that the infecting virus is SIV and not HIV-2 and that this virus, SIV_HU, is closely related to the SIV_B670 strain with which the researcher primarily worked. Six percent or more sequence variability can be seen in env sequences from single SIV-infected animals¹⁹; therefore, the 94 percent sequence homology in the env sequence of SIV_HU and SIV_B670 is highly indicative of a close genetic relation. SIV_B670 had never been handled or grown in our laboratory before SIV_HU was isolated.

The SIV-infected researcher remains asymptomatic with no clinical or laboratory evidence of immunodeficiency 3 1/2 years after seroconversion in April 1990. CD4+ counts have been obtained twice yearly since April 1992 and have all exceeded 800 cells per cubic millimeter, or 45 percent. The clinical outcome of SIV infection in a human is unknown. It might be expected to be similar to that of its closest human counterpart, HIV-2, which is believed to be less pathogenic than HIV-1²⁰. The small viral burden and the inability to recover the virus consistently by culture or PCR may be indicative of a good prognosis. Further characterization of the SIV_HU isolate is under way. Preliminary data show a premature truncation in the nef gene of SIV_HU (but not in that of SIV_B670). This deletion might explain the small viral burden in our subject, which is consistent with observations in monkeys inoculated with SIV deleted in the nef gene²¹. Truncation of the transmembrane protein²² and differences in cell tropism are also being examined. We are trying to determine whether this patient's specific immune or cellular mechanisms are protective against SIV or other lentiviruses such as HIV-1.

Our difficulty in isolating virus from this subject (only 1 of 10 attempts was successful) parallels the experience of Gao et al.,¹³ who were unsuccessful in culturing a virus from two West Africans seropositive for HIV-2. HIV-2 is also difficult to detect by PCR and to isolate from infected, asymptomatic patients with CD4+ counts above 500 per cubic millimeter²³. Such difficulty in isolating the virus may be due to a low level of circulating virus or may be a consequence of the distribution of the virus in the tissue -- for example, it may be sequestered in lymph nodes or primarily infect macrophages. Alternatively, human host factors may suppress SIV replication. We succeeded in isolating the virus only in a primary culture after the depletion of CD8+ cells, whereas culture of these same CD8+-depleted cells with normal PBMCs yielded no virus. This failure may be due to the presence of inhibitory CD8+ cells in the culture^24,25. In addition, our inability to detect SIV consistently by PCR, despite using SIV_HU-specific primers and probes (with a minimal sensitivity of 15 copies and with multiple testing of increasing template concentrations) suggests a low level of circulating virus.

Although our subject's increasing antibody titer suggests continued viral replication, the similarity of the env sequences in samples obtained in April, June, and October 1992 is consistent with the presence of a low replication rate. Furthermore, the similarity of the env sequences in the clones derived in vivo and in five clones derived in vitro suggests that this isolate is not a minor species. Further sequencing of additional clones will allow us to address the possibility of the development of a quasi-species.

Although we did not identify a specific exposure in this case as we did in our earlier case report of a person who seroconverted to SIV after a needle stick,¹⁴ departures from recommended procedures to prevent SIV infection in the laboratory were documented²⁶. This report reemphasizes the need for researchers to adhere to recommended precautions when working with SIV-infected material. This case might not be an isolated event. An anonymous survey conducted in collaboration with the Office of AIDS Research and several institutes at the National Institutes of Health to investigate seroreactivity among U.S. SIV researchers showed that 3 of 472 researchers (0.6 percent) tested had antibodies to HIV-2 and SIV²⁷. Because of the anonymous design of the survey, it is possible that one or both of the researchers we describe are among the three seropositive workers. A study is being initiated among SIV researchers and animal caretakers to investigate SIV seropositivity, define specific types of exposure associated with it, and assess clinical outcomes.

Supported in part by grants (RR00165 and RR00164) from the National Center for Research Resources to the Yerkes and Tulane Regional Primate Centers.

We are indebted to Dr. Gerald Myers of Los Alamos National Laboratory for analyzing the viral sequences; to Dr. Chin-Yih Ou of the Centers for Disease Control and Prevention (CDC) for reviewing the data; to Drs. Jonathan Kaplan, Brian Mahy, and Gerald Schochetman of the CDC for critically reviewing the manuscript; and to Mr. John O'Connor of the CDC for excellent editorial assistance.

Source Information

From the Retrovirus Diseases Branch, Division of Viral and Rickettsial Diseases (R.F.K., W.H., T.R., T.W., W.M.S., T.M.F.), and the Laboratory Investigations Branch, Division of HIV/AIDS, National Center for Infectious Diseases (J.R.G., B.P.), Centers for Disease Control and Prevention, Atlanta; Yerkes Regional Primate Research Center, Emory University, Atlanta (H.M.M.); and Tulane Regional Primate Center, Tulane University, Covington, La. (M.M.-C.).

Address reprint requests to Dr. Khabbaz at the Centers for Disease Control and Prevention, Mailstop G-03, 1600 Clifton Rd., Atlanta, GA 30333.

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