Simian T-lymphotropic virus diversity among nonhuman primates, Cameroon.

Cross-species transmission of retroviruses is common in Cameroon. To determine risk for simian T-cell lymphotropic virus (STLV) transmission from nonhuman primates to hunters, we examined 170 hunter-collected dried blood spots (DBS) from 12 species for STLV. PCR with generic tax and group-specific long terminal repeat primers showed that 12 (7%) specimens from 4 nonhuman primate species were infected with STLV. Phylogenetic analyses showed broad diversity of STLV, including novel STLV-1 and STLV-3 sequences and a highly divergent STLV-3 subtype found in Cercopithecus mona and C. nictitans monkeys. Screening of peripheral blood mononuclear cell DNA from 63 HTLV-seroreactive, PCR-negative hunters did not identify human infections with this divergent STLV-3. Therefore, hunter-collected DBS can effectively capture STLV diversity at the point where pathogen spillover occurs. Broad screening using this relatively easy collection strategy has potential for large-scale monitoring of retrovirus cross-species transmission among highly exposed human populations.

Ancient, independent evolution and distinct molecular features of the novel human T-lymphotropic virus type 4.

BACKGROUND: Human T-lymphotropic virus type 4 (HTLV-4) is a new deltaretrovirus recently identified in a primate hunter in Cameroon. Limited sequence analysis previously showed that HTLV-4 may be distinct from HTLV-1, HTLV-2, and HTLV-3, and their simian counterparts, STLV-1, STLV-2, and STLV-3, respectively. Analysis of full-length genomes can provide basic information on the evolutionary history and replication and pathogenic potential of new viruses. RESULTS: We report here the first complete HTLV-4 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocyte DNA from an HTLV-4-infected person. The HTLV-4(1863LE) genome is 8791-bp long and is equidistant from HTLV-1, HTLV-2, and HTLV-3 sharing only 62-71% nucleotide identity. HTLV-4 has a prototypic genomic structure with all enzymatic, regulatory, and structural proteins preserved. Like STLV-2, STLV-3, and HTLV-3, HTLV-4 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains unique c-Myb and pre B-cell leukemic transcription factor binding sites. Like HTLV-2, the PDZ motif important for cellular signal transduction and transformation in HTLV-1 and HTLV-3 is missing in the C-terminus of the HTLV-4 Tax protein. A basic leucine zipper (b-ZIP) region located in the antisense strand of HTLV-1 and believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-4. Detailed phylogenetic analysis shows that HTLV-4 is clearly a monophyletic viral group. Dating using a relaxed molecular clock inferred that the most recent common ancestor of HTLV-4 and HTLV-2/STLV-2 occurred 49,800 to 378,000 years ago making this the oldest known PTLV lineage. Interestingly, this period coincides with the emergence of Homo sapiens sapiens during the Middle Pleistocene suggesting that early humans may have been susceptible hosts for the ancestral HTLV-4. CONCLUSION: The inferred ancient origin of HTLV-4 coinciding with the appearance of Homo sapiens, the propensity of STLVs to cross-species into humans, the fact that HTLV-1 and -2 spread globally following migrations of ancient populations, all suggest that HTLV-4 may be prevalent. Expanded surveillance and clinical studies are needed to better define the epidemiology and public health importance of HTLV-4 infection.

Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir.

BACKGROUND: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. METHODS AND FINDINGS: We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS: This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.

Clinical and virological characterization of persistent human infection with simian foamy viruses.

Persons occupationally exposed to nonhuman primates (NHPs) can be persistently infected with simian foamy virus (SFV). The clinical significance and person-to-person transmissibility of zoonotic SFV infection is unclear. Seven SFV-infected men responded to annual structured interviews and provided whole blood, oral, and urogenital specimens for study. Wives were tested for SFV infection. Proviral DNA was consistently detected by PCR in PBMCs of infected men and inconsistently in oral or urogenital samples. SFV was infrequently cultured from their PBMCs and throat swabs. Despite this and a long period of intimate exposure (median 20 years), wives were SFV negative. Most participants reported nonspecific symptoms and diseases common to aging. However, one of two persons with mild thrombocytopenia had clinically asymptomatic nonprogressive, monoclonal natural killer cell lymphocytosis of unclear relationship to SFV. All participants worked with NHPs before 1988 using mucocutaneous protection inconsistently; 57% described percutaneous injuries involving the infecting NHP species. SFV likely transmits to humans through both percutaneous and mucocutaneous exposures to NHP body fluids. Limited follow-up has not identified SFV-associated illness and secondary transmission among humans.

Naturally acquired simian retrovirus infections in central African hunters.

BACKGROUND: Hunting and butchering of wild non-human primates infected with simian immunodeficiency virus (SIV) is thought to have sparked the HIV pandemic. Although SIV and other primate retroviruses infect laboratory workers and zoo workers, zoonotic retrovirus transmission has not been documented in natural settings. We investigated zoonotic infection in individuals living in central Africa. METHODS: We obtained behavioural data, plasma samples, and peripheral blood lymphocytes from individuals living in rural villages in Cameroon. We did serological testing, PCR, and sequence analysis to obtain evidence of retrovirus infection. FINDINGS: Zoonotic infections with simian foamy virus (SFV), a retrovirus endemic in most Old World primates, were identified in people living in central African forests who reported direct contact with blood and body fluids of wild non-human primates. Ten (1%) of 1099 individuals had antibodies to SFV. Sequence analysis from these individuals revealed three geographically-independent human SFV infections, each of which was acquired from a distinct non-human primate lineage: De Brazza's guenon (Cercopithecus neglectus), mandrill (Mandrillus sphinx), and gorilla (Gorilla gorilla), two of which (De Brazza's guenon and mandrill) are naturally infected with SIV. INTERPRETATION: Our findings show that retroviruses are actively crossing into human populations, and demonstrate that people in central Africa are currently infected with SFV. Contact with non-human primates, such as happens during hunting and butchering, can play a part in the emergence of human retroviruses and the reduction of primate bushmeat hunting has the potential to decrease the frequency of disease emergence.

Nigerian HIV type 2 subtype A and B from heterotypic HIV type 1 and HIV type 2 or monotypic HIV type 2 infections.

The presence of HIV-2 in Nigeria has been confirmed serologically, but not genetically. To determine the frequency of HIV-2 infections and the dynamics between HIV-1 and HIV-2 in 35 of 36 Nigerian states, 420 blood samples were collected in 1999. Antibodies to HIV-1 and HIV-2 were detected by EIA and seroreactivity was confirmed with the INNO-LIA HIV Line Assay. The frequency of HIV-2 was 4.3% (18 of 420), with 3.8% (16 of 420) HIV-1 and HIV-2 (HIV-1/2) heterotypic and 0.5% (2 of 420) HIV-2 homotypic infections. The presence of HIV-2 subtype B in the two monotypic HIV-2 infections and subtype A in 11 (68.8%) of 16 HIV-1/2 dually seropositive samples was established by sequencing and phylogenetic analysis. HIV-2 subtype B viruses were not found in any of the HIV-1/2 dual infections, and HIV-2 subtype A strains were not identified in either of the two monotypic HIV-2 infections. Since our sample size was small and represented only convenience samples, larger randomized studies will be needed to better understand the dynamics of infection between HIV-1 and different HIV-2 subtypes and to determine whether significant biological differences exist among the HIV- 2 subtypes.

Chronic HIV-2 infection protects against total CD4+ cell depletion and rapid disease progression induced by SHIV89.6p challenge.

OBJECTIVE: To better understand HIV-1 sexual transmission risk, we have studied the susceptibility of HIV-2-exposed, uninfected (EU) female pig-tailed macaques to intravaginal (IVAG) re-challenge with the homologous HIV-2 strain, followed by heterologous SHIV89.6p. METHODS: Nine female macaques, previously protected by a post-exposure prophylaxis (PEP) regimen, along with one mock-treated EU animal, were re-exposed to HIV-2 by the IVAG route approximately 1.5 years later. A single follow-up challenge was performed approximately 1 year later with SHIV89.6p to assess susceptibility of chronic HIV-2-infected animals to further re-infection and pathogenic effects with a heterologous virus, somewhat mimicking HIV-1. RESULTS: Eight of ten macaques (80%) became infected systemically with HIV-2, and plasma or cervicovaginal vRNA levels did not appreciably differ from prior historic non-PEP control macaques. Interestingly, all eight HIV-2-infected females were susceptible to SHIV89.6p infection by either intravenous (n = 4) or IVAG exposure (n = 4) after one inoculation. Plasma vRNA levels in these groups were controlled by week 8 and there were no decrease in CD4+ T cells > 50%. The remaining two HIV-2 EU macaques, inoculated intrarectally with SHIV89.6p, were unable to control virus replication and succumbed to disease by week 25 or week 61. CONCLUSIONS: Our findings demonstrate that successful PEP regimens to prevent an initial infection do not have any lasting protective effects. The observed lack of cross-protection against SHIV89.6p transmission among chronic HIV-2-infected macaques provides modeling support for limited epidemiologic data indicating that human HIV-2 infection does not protect against HIV-1 infection, but may serve to alter overt clinical outcome.

Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis.

Limited information is available on the activity of antiretroviral drugs against human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) strains to guide their use in treatment or prophylaxis. We evaluated the antiviral activity of 16 approved drugs and one experimental drug, AMD3100, against two wild-type HIV-2 (ROD and EHO) isolates, two strains of SIV (mac251 and B670), and two strains of simian-human immunodeficiency virus (SHIV) that contain the reverse transcriptase (RTSHIV) or envelope glycoprotein (SHIV89.6) of human immunodeficiency virus type 1 (HIV-1) in a SIV(mac239) background. Drug susceptibility was measured conventionally by the MT-4/MTT assay, and results were analysed as fold changes in 50% effective concentration (EC50) relative to the EC50 for HIV-1 (IIIB). The nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, lamivudine, stavudine, didanosine, zalcitabine and abacavir as well as the nucleotide reverse transcriptase inhibitor tenofovir retained full activity against all six viruses except for SIV and SHIV89.6 that showed low-level resistance to didanosine. The protease inhibitors (PIs) ritonavir, indinavir, saquinavir and nelfinavir were found to be active against some HIV-2 or SIV strains. However, a significant reduction in susceptibility was seen with indinavir against SHIV89.6 (3.3-fold), and with amprenavir against HIV-2(ROD) (8.8-fold). All viruses except for RTSHIV showed a >200-fold decrease in susceptibility for the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz, indicating high-level resistance. AMD3100, a CXCR4 antagonist, was active against HIV-2 and SHIV89.6, a finding consistent with the use of the CXCR4 co-receptor by these isolates, but was inactive against SIV strains. In contrast, enfuvirtide (T-20) was active against SHIV89.6 but had reduced inhibitory activity against both HIV-2 and SIV strains predicting little therapeutic value against these viruses. These findings support the use of NRTIs, tenofovir, but not NNRTIs, for treating HIV-2-infected persons or for prophylaxis against HIV-2 and SIV. The clinical significance of the low-level resistance of HIV-2 and SIV to some PIs is unclear. Co-receptor antagonists such as AMD3100 show promising anti-HIV-2 therapeutic modalities. Both AMD3100 and enfuvirtide could be used for prophylaxis against SHIV89.6.

New HIV type 1 CRF01_AE/B recombinants displaying unique distribution of breakpoints from incident infections among injecting drug users in Thailand.

The goals of this study were to identify and characterize recombinant human immunodeficiency virus type 1 (HIV-1) genomes among incident infections in a prospective cohort study of injecting drug users (IDUs) in Bangkok, Thailand. Through cross-sectional, comparative phylogenetic analysis of the protease and env (C2-V4) gene regions, subtype discordance was observed in HIV-1 sequences from 4 of 111 IDUs (3.5%). Near-full-length HIV-1 genome sequences of the four strains revealed that in all four, the gp120 sequences clustered with a CRF01_AE prototype, while the remainder of the genomes displayed distinct mosaic patterns, with multiple breakpoints between HIV-1 CRF01_AE and subtype B-like regions. Two of the four HIV-1 recombinant strains displayed a nearly identical mosaic structure, suggesting the possible emergence and spread of a potentially new circulating recombinant form of HIV-1. Further characterization of these and other recombinant genomes through long-term follow-up will be important in understanding the generation of viral diversity and escape from the hosts immune responses. This information will be especially important for vaccine development.

Molecular analysis in support of an investigation of a cluster of HIV-1-infected women.

An investigation of a possible single-source sexual transmission case was conducted in upstate New York in 1997-1998 (MMWR 1999;48:413-416). Of 42 primary female contacts with the putative male index case, 13 tested positive for HIV infection. Blood was available for DNA sequencing (C2V3C3 region of the env gene and the p17-coding region of gag) from 10 of the 13 women, 1 HIV-infected secondary contact, and 2 HIV-infected persons from the community, but not from the index cam. Phylogenetic and distance analyses were performed with the inclusion of reference HIV subtype strains for both the env and gag gene regions, as was the two regions combined. A high degree of relatedness was found among DNA sequences of the 10 primary contacts that excluded reference strains, the secondary contact, and the community HIV control subjects. In conclusion, phylogenetic analysis of HIV strains in an epidemiologic investigation is highly useful in support of cluster identification, even without sampling from the putative index patient.

Prevalence of drug resistance-related polymorphisms in treatment-naive individuals infected with nonsubtype B HIV type 1 in Cameroon.

Mutations associated with the use of protease (PR) and reverse transcriptase (RT) inhibitors have been mostly mapped for HIV-1 subtype B. The prevalence of these mutations in drug-naive HIV-1 subtype B-infected individuals is low but occurs at high frequencies in treated individuals. To determine the prevalence of treatment-associated mutations in non-B viruses, we analyzed a 1613-bp pol region of specimens collected from 57 HIV-1-infected treatment-naive individuals from Cameroon. Of the 57 HIV-1 sequences, 43 belonged to CRF02-AG, two to CRF11-cpx, six to subtype A, one to subtype D, and five were unclassifiable. Of the 57 PR sequences, 100% contained at least one codon change giving substitutions at positions 10, 11, 16, 20, 33, 36, 60, 62, 64, 69, 77, and 89. These substitutions gave the following prevalence pattern, 36I/L (100%, 57/57) >89M/I (98%, 56/57)>69K/R (93%, 53/57)>20I/R (89%, 51/57)>16E (16%, 9/57)>64M (12%, 7/57)>10I (11%, 6/57)>11V (5%, 3/57)=62V (5%, 3/57)=77I (5%, 3/57)>233F/V (4%, 2/57)=60E (4%), which differed significantly from subtype B at positions 20, 36, 69, and 89. All but one (98%) of the 57 RT sequences (438 amino acid residues) carried substitutions located at codons 39A (7%), 43E (7%), 122E (7%), 312Q (2%), 333E (2%), 335C/D (89%), 356K (89%), 358K (14%), 365I (2%), 371V (81%), 376S (11%), or 399D (4%); the frequency of these substitutions ranged from <0.5% to 4% in RT of subtype B. The high prevalence of minor mutations associated with protease inhibitors (PI) and reverse transcriptase inhibitors (RTI) represents natural polymorphisms. HIV-1 PR and RT sequences from antiretroviral (ARV)-naive HIV-infected persons in Cameroon are important for monitoring the development of resistance to PIs and RTIs as such mutations could lead to treatment failures in individuals undergoing ARV therapy.

Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection.

HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.

Coinfection with HIV-1 and simian foamy virus in West Central Africans.

Frequent infection with zoonotic simian foamy virus (SFV) has been reported among HIV-negative primate hunters in rural Cameroon. Plasma samples obtained from urban commercial sex workers (CSWs; n = 139), patients with sexually transmitted diseases (n = 41), and blood donors (n = 179) in the Democratic Republic of Congo [formerly known as Zaire] and Cameroon were tested for SFV and HIV-1 infection. One CSW and one blood donor were found to be seropositive for both SFV and HIV-1, thereby documenting what are, to our knowledge, the first reported cases of dual SFV and HIV infection. The findings of the present study suggest opportunities for bloodborne and sexual transmission of SFV and highlight the importance of defining the clinical consequences of dual infections.

Short communication: no evidence of occult SHIV infection as demonstrated by CD8+ cell depletion after chemoprophylaxis-induced protection from mucosal infection in rhesus macaques.

Preexposure prophylaxis (PrEP) with antiretroviral drugs constitutes a promising strategy for HIV prevention. Potent PrEP regimens with reverse transcriptase inhibitors can prevent detectable SHIV infection in a repeated low-dose macaque model that resembles human transmission, supporting plans to quickly move this approach into human trials. However, the possibility remains that extremely low levels of virus replication could nonetheless occur during PrEP and seed viral reservoirs in tissues. Therefore, seemingly protected macaques may harbor occult virus that may be initially contained by cytotoxic T cells, but could emerge later. To explore this possibility, we studied whether CD8(+) cells suppress viremia in four rhesus macaques apparently protected by daily or intermittent Truvada (FTC and tenofovir) during 14 low-dose, rectal SHIV(SF162P3) challenges and during a subsequent drug washout period. CD8(+) cells were efficiently ablated with antibodies in these and two additional control macaques that were previously infected but had reached undetectable virus set points. During 4 weeks of follow-up, all four macaques remained free of plasma viremia and provirus in blood lymphocytes. In contrast, plasma viremia resurged to 10(6) to 10(7) copies per milliliter within 2 weeks in both control macaques. Thus, these results indicate that the undetectable viremia in the PrEP-protected macaques was not due to CD8(+) cells that were containing a low-level infection. Rather, the PrEP treatment created conditions in which infection was prevented, eliminated, or controlled by unknown mechanisms. These data provide important information for PrEP usage to prevent HIV transmission, and fully support the continued pursuit of PrEP prevention measures in humans.

Repetitive exposures with simian/human immunodeficiency viruses: strategy to study HIV pre-clinical interventions in non-human primates.

BACKGROUND: Non-human primate models for human immunodeficiency virus (HIV) infection represent a valuable pre-clinical tool to evaluate interventions (e.g., topical microbicides, vaccines, and chemoprophylaxis) designed to prevent transmission or slow disease progression after infection. Standard transmission models use a single-dose exposure with high, non-physiologic levels of virus to approach 100% infection rates of control animals. These single-exposure models do not represent the circumstances of mucosal HIV transmission in humans and may result in misleading data with regard to intervention efficacy. Therefore, we have developed a repetitive mucosal exposure model using doses of virus that better reflects human exposures. METHODS: The virus used for these evaluations was simian-human immunodeficiency virus [SHIVSF162P3 (R5-using, subtype B HIV-1 envelope)] and the virus dose used (approximately 10(5)-10(6) viral particle equivalents or approximately 10 tissue culture infectious doses per exposure) approximates viral loads observed in the semen during acute HIV-1 infection. Using the repeated mucosal exposure approach, we have evaluated a candidate vaginal microbicide (cellulose acetate phthalate, CAP) given 15 minutes prior to each weekly virus exposure. Pig-tailed macaques were exposed weekly by vaginal inoculations with and without microbicide until systemic viral RNA was detected. RESULTS: Groups of naïve control monkeys were infected after an average of three to four exposures for the vaginal route of inoculation. Data from the first application of this monkey model to evaluate the topical microbicide CAP suggested that protection from SHIV infection was possible with three of four CAP-treated monkeys remaining uninfected after 12 exposures (P = 0.015). CAP efficacy was markedly improved from 66% in a previous single-dose virus exposure study to 92% in this repeated exposure system. CONCLUSIONS: Our experience with using repetitive virus exposures to study topical microbicides and the findings to date from this study provides a basis to refine monkey models to more closely resemble human exposure during HIV transmission. This model may be highly relevant to pre-clinical evaluation for a variety of therapeutic interventions which is discussed here.

Ancient origin and molecular features of the novel human T-lymphotropic virus type 3 revealed by complete genome analysis.

Human T-lymphotropic virus type 3 (HTLV-3) is a new virus recently identified in two primate hunters in Central Africa. Limited sequence analysis shows that HTLV-3 is distinct from HTLV-1 and HTLV-2 but is genetically similar to simian T-lymphotropic virus type 3 (STLV-3). We report here the first complete HTLV-3 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocytes from an HTLV-3-infected person. The HTLV-3(2026ND) genome is 8,917 bp long and is genetically equidistant from HTLV-1 and HTLV-2, sharing about 62% identity. Phylogenetic analysis of all gene regions confirms this relationship and shows that HTLV-3 falls within the diversity of STLV-3, suggesting a primate origin. However, HTLV-3(2026ND) is unique, sharing only 87% to 92% sequence identity with STLV-3. SimPlot and phylogenetic analysis did not reveal any evidence of genetic recombination with either HTLV-1, HTLV-2, or STLV-3. Molecular dating estimates that the ancestor of HTLV-3 is as old as HTLV-1 and HTLV-2, with an inferred divergence time of 36,087 to 54,067 years ago. HTLV-3 has a prototypic genomic structure, with all enzymatic, regulatory, and structural proteins preserved. Like STLV-3, HTLV-3 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains a unique activator protein-1 transcription factor upstream of the 21-bp repeat elements. A PDZ motif, like that in HTLV-1, which is important for cellular signal transduction and transformation, is present in the C terminus of the HTLV-3 Tax protein. A basic leucine zipper region located in the antisense strand of HTLV-1, believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-3. The ancient origin of HTLV-3, the broad distribution of STLV-3 in Africa, and the propensity of STLVs to cross species into humans all suggest that HTLV-3 may be prevalent and support the need for expanded surveillance for this virus.

Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges.

We examined the efficacy of tenofovir disoproxil fumarate (TDF) in blocking simian human immunodeficiency virus (SHIV) infection in Chinese rhesus macaques. Once weekly for 14 weeks or until a macaque became infected, 12 male macaques were inoculated intrarectally with amounts of SHIV(SF162P3) (10 median tissue culture infective doses; 3.8 x 10(5) virus particles) that were approximately 5-fold higher than the human immunodeficiency virus type 1 RNA levels noted in human semen during an acute infection. Of the 12 macaques, 4 received oral TDF daily, 4 received oral TDF once weekly, and 4 (control animals) received no TDF. The control animals became infected after receiving a median of 1.5 virus inoculations; macaques receiving TDF daily (1 macaque remained uninfected after 14 inoculations) and those receiving TDF weekly became infected after a median duration of 6.0 and 7.0 weeks, respectively. Although infection was delayed in treated macaques, compared with control macaques, the differences were not statistically significant (P=.315); however, the study was limited by the small numbers of animals evaluated and the variability in blood levels of TDF that resulted from oral dosing. These data demonstrate that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.

Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates.

A nonhuman-primate model of human immunodeficiency virus type 1 (HIV-1) infection that more closely emulates human heterosexual transmission by use of multiple exposures to low doses of virus is critical to better evaluate intervention strategies that include microbicides or vaccines. In this report, we describe such a system that uses female pig-tailed macaques exposed vaginally to a CCR5-using simian-human immunodeficiency virus (SHIV(SF162P3)) at weekly intervals. Results of dose-titration experiments indicated that 3 once-weekly exposures to 10 tissue culture infectious doses of SHIV(SF162P3) resulted in consistent transmission of virus and establishment of systemic infection. The efficacy of cellulose acetate phthalate (CAP) as a vaginal microbicide was evaluated by applying it to the vaginal vault of macaques (n = 4) 15 min before each weekly exposure to SHIV(SF162P3). One conclusion that can be drawn from the data derived from multiple exposures to virus is that CAP prevented infection in 12 of 13 possible chances for infection, over the course of 39 total exposures. Our findings provide a basis to refine monkey models for transmission of HIV-1, which may be relevant to preclinical evaluation for therapeutic interventions.

Divergent HIV and simian immunodeficiency virus surveillance, Zaire.

Recent HIV infection or divergent HIV or simian immunodeficiency virus (SIV) strains may be responsible for Western blot-indeterminate results on 70 serum samples from Zairian hospital employees that were reactive in an enzyme immunoassay. Using universal polymerase chain reaction HIV-1, HIV-2, and SIV primers, we detected 1 (1.4%) HIV-1 sequence. Except for 1 sample, no molecular evidence for unusual HIV- or SIV-like strains in this sampling was found.