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Simian Immunodeficiency Virus (simian + immunodeficiency_virus)
Selected AbstractsDeveloping an HIV cytotoxic T-lymphocyte vaccine: issues of CD8 T-cell quantity, quality and locationJOURNAL OF INTERNAL MEDICINE, Issue 1 2009D. Masopust Abstract. Issues of quantity, quality and location impact the ability of CD8 T cells to mediate protection from infection. These issues are considered in light of human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccination. Methods are reviewed that result in 100- to 1000-fold higher frequencies of vaccine-specific memory CD8 T cells than that achieved by current HIV/SIV vaccine approaches. Data demonstrating that location within mucosal tissues has a direct impact on memory CD8 T-cell function are discussed. Arguments are made that establishing memory CD8 T cells within mucosal sites of transmission, a priori to natural infection, may be essential for conferring optimal and rapid protection. Lastly, it is proposed that heterologous prime-boost vaccination with recombinant live replicating vectors, which has the potential to induce tremendous numbers of cytolytic memory CD8 T cells within mucosal tissues, would provide a far more stringent test of the hypothesis that memory CD8 T cells could, in principal, form the basis for a preventative HIV vaccine. [source] Expression of CD8, identifies a distinct subset of effector memory CD4+ T lymphocytesIMMUNOLOGY, Issue 2 2006Iole Macchia Summary Circulating CD4+ CD8+ T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4+ CD8+ T cells in rhesus macaques. Two distinct populations of CD4+ CD8+ T cells were identified: the dominant one was CD4hi CD8lo and expressed the CD8,, homodimer, while the minor population was CD4lo CD8hi and expressed the CD8,, heterodimer. The majority of CD4hi CD8,lo T cells exhibited an activated effector/memory phenotype (CCR5lo CD7, CD28, HLA-DR+) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4hi CD8,lo T cells compared to single-positive CD4+ T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4hi CD8,lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4hi CD8,lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4+ T cells expressing CD8, represent an effector/memory subset of CD4+ T cells and that this cell population can be depleted during the course of SIV infection. [source] Viral interleukin-6 encoded by rhesus macaque rhadinovirus is associated with lymphoproliferative disorder (LPD)JOURNAL OF MEDICAL PRIMATOLOGY, Issue 2009B.U. Orzechowska Abstract Background, Rhesus macaques (RM) co-infected with simian immunodeficiency virus (SIV) and rhesus macaque rhadinovirus (RRV) develop abnormal cellular proliferations characterized as extra-nodal lymphoma and retroperitoneal fibromatosis (RF). RRV encodes a viral interleukin-6 (vIL-6), much like Kaposi's sarcoma-associated herpesvirus, and involvement of the viral cytokine was examined in proliferative lesions. Methods, Formalin fixed tissue from RM co-infected with SIV and RRV were analyzed for RRV genomes by in situ hybridization and RRV vIL-6 expression by immunofluorescence analysis. Results, In situ hybridization analysis indicated that RRV is present in both types of lesions. Immunofluorescence analysis of different lymphomas and RF revealed positive staining for vIL-6. Similarly to KS, RF lesion is positive for vimentin, CD117 (c-kit), and smooth muscle actin (SMA) and contains T cell, B cell and monocytes/macrophage infiltrates. Conclusions, Our data support the idea that vIL-6 may be critical to the development and progression of lymphoproliferative disorder in RRV/SIV-infected RM. [source] Therapeutic immunization with Modified Vaccinia Virus Ankara (MVA) vaccines in SIV-infected rhesus monkeys undergoing antiretroviral therapyJOURNAL OF MEDICAL PRIMATOLOGY, Issue 1 2007Klaus Überla Abstract Background, The long-term benefits of highly active antiretroviral therapy in HIV-infected patients are limited by emergence of drug-resistant variants and side effects. Therefore, we studied the concept of therapeutic immunization in 18 rhesus monkeys infected with a highly pathogenic simian immunodeficiency virus (SIV) swarm. Methods, Monkeys were treated with the reverse transcriptase inhibitor (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for 19 weeks starting 10 days after infection. After suppression of viremia, one group of monkeys was immunized with recombinant modified vaccinia virus Ankara (MVA) vectors expressing gag-pol and env. A second group received MVA vectors expressing the regulatory genes tat, rev and nef, while a third group was not immunized. Results, Immunization with gag-pol and env expressing MVA enhanced SIV antibody titers. Following discontinuation of PMPA treatment, a rebound in viral load was observed. However, in three of six monkeys immunized with MVA gag-pol and MVA env, and two of six monkeys immunized MVA expressing regulatory genes set point RNA levels were below or close to a threshold level of 104 RNA copies/ml, while only one of six unvaccinated monkeys maintained such low RNA levels. Conclusions, Although a subset of animals seem to benefit from therapeutic immunization with MVA vectors, the difference in set point RNA levels between the groups did not reach statistical significance. [source] Gene expression profiling of gut mucosa and mesenteric lymph nodes in simian immunodeficiency virus-infected macaques with divergent disease courseJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4-5 2006M.D. George Abstract Background, Although the majority of drug-naïve HIV-infected patients develop acquired immunodeficiency syndrome (AIDS), a small percentage remains asymptomatic without therapeutic intervention. Methods, We have utilized the simian immunodeficiency virus (SIV)-infected rhesus macaque model to gain insights into the molecular mechanisms of long-term protection against simian AIDS. Results, Chronically SIV-infected macaques with disease progression had high viral loads and CD4+ T-cell depletion in mucosal tissue and peripheral blood. These animals displayed pathologic changes in gut-associated lymphoid tissue (GALT) and mesenteric lymph node that coincided with increased expression of genes associated with interferon induction, inflammation and immune activation. In contrast, the animal with long-term asymptomatic infection suppressed viral replication and maintained CD4+ T cells in both GALT and peripheral blood while decreasing expression of genes involved in inflammation and immune activation. Conclusions, Our findings suggest that reduced immune activation and effective repair and regeneration of mucosal tissues correlate with long-term survival in SIV-infected macaques. [source] Quantitative evaluation of Enterocytozoon bieneusi infection in simian immunodeficiency virus-infected rhesus monkeysJOURNAL OF MEDICAL PRIMATOLOGY, Issue 2 2003K. Sestak Abstract: The association of the microsporidia Enterocytozoon bieneusi with chronic diarrhea and wasting in individuals with acquired immunodeficiency syndrome (AIDS) has been demonstrated. The disease caused by E. bieneusi has been linked to decreased levels of circulating CD4+ T lymphocytes. In this study, we investigated the relationship between the extent of excretion of E. bieneusi in feces of simian immunodeficiency virus (SIV)-infected juvenile macaques and the CD4+ T lymphocyte counts in the peripheral blood. Twelve juvenile rhesus monkeys (Macaca mulatta) were intravenously inoculated with the pathogenic molecular clone SIVmac239. Numbers of CD4+ T lymphocytes were assessed by three-color flow cytometry. The presence of E. bieneusi DNA in feces was assessed by nested PCR. In addition, selected samples of feces were examined by competitive quantitative PCR to assess the level of E. bieneusi infection. Low (n = 5) to undetectable (n = 7) quantities of E. bieneusi were present in feces of the twelve animals in prior to inoculation with SIV. After SIV inoculation the number of animals shedding E. bieneusi increased (n = 10) as did the quantity of E. bieneusi shedding in the feces. Of the twelve juvenile animals, five animals died within 8 months post-SIV inoculation with symptoms of AIDS. Four of the five deceased animals showed shedding of E. bieneusi DNA in feces (,100 spores/g) for at least three consecutive months. Increased number of E. bieneusi in feces was accompanied by decreased counts of circulating CD4+ T lymphocytes and increased SIV plasma viral load. [source] Effect of vaccination with recombinant modified vaccinia virus Ankara expressing structural and regulatory genes of SIVmacJ5 on the kinetics of SIV replication in cynomolgus monkeysJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4 2001Donatella R.M. Negri The efficacy of a multicomponent vaccination with modified vaccinia Ankara constructs (rMVA) expressing structural and regulatory genes of simian immunodeficiency virus (SIVmac251/32H/J5) was investigated in cynomolgus monkeys, following challenge with a pathogenic SIV. Vaccination with rMVA-J5 performed at week 0, 12, and 24 induced a moderate proliferative response to whole SIV, a detectable humoral response to all but Nef SIV antigens, and failed to induce neutralizing antibodies. Two months after the last boost, the monkeys were challenged intravenously with 50 MID50 of SIVmac251. All control monkeys, previously inoculated with non-recombinant MVA, were infected by week two and seroconverted by weeks four to eight. In contrast a sharp increase of both humoral and proliferative responses at two weeks post-challenge was observed in vaccinated monkeys compared to control monkeys. Although all vaccinated monkeys were infected, vaccination with rMVA-J5 appeared to partially control viral replication during the acute and late phase of infection as judged by cell- and plasma-associated viral load. [source] Mucosal challenge of Macaca nemestrina with simian immunodeficiency virus (SIV) following SIV nucleocapsid mutant DNA vaccination*JOURNAL OF MEDICAL PRIMATOLOGY, Issue 3-4 2000Robert J. Gorelick A simian immunodeficiency virus (SIV)(Mne) DNA clone was constructed that produces viruses containing a four amino acid deletion in the second zinc finger of the nucleocapsid (NC) domain of the Gag polyprotein. Viruses produced from this clone, although non-infectious both in vitro and in vivo, complete a majority of the steps in a single retroviral infection cycle. Eight pig-tailed macaques (Macaca nemestrina) were inoculated intramuscularly and subcutaneously three times over the course of 24 weeks with the NC mutant expressing DNA. These macaques, and four controls, were then challenged mucosally (intrarectally) with the homologous virus (SIV Mne CL E11S) and monitored for evidence of infection and clinical disease. Prior to challenge, a measurable humoral immune response was noted in four of eight immunized macaques. After challenge, all 12 macaques became infected, although four immunized animals greatly restricted their viral replication, and one immunized animal that controlled replication remains antibody negative. No disease has been evidence during the 46-week period of monitoring after challenge. [source] Antibody convergence along a common idiotypic axis in immunodeficiency virus and hepatitis C virus infectionsJOURNAL OF MEDICAL VIROLOGY, Issue 1 2002Michael D. GrantArticle first published online: 29 NOV 200 Abstract The anti-idiotypic antibody 1F7 selectively binds antibodies against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) gag, pol, and env proteins. We tested anti-hepatitis C virus (HCV) antibodies to investigate selection of the 1F7 idiotype on antibodies against other chronic pathogens. Twelve of 15 HCV-seropositive individuals co-infected with HIV had detectable antibodies against recombinant HCV core, 4 against HCV NS4 protein, and 3 against HCV NS3 protein. All four HCV-seropositive, non-HIV-infected individuals had antibodies against HCV core and NS4, while 3 had antibodies against NS3. The 1F7 idiotype was frequently present on antibodies against each of the HCV antigens in the HIV co-infected and non-HIV-infected groups. Antibodies against HCV, including antibodies recognizing the putative principal neutralizing determinant of HCV E2 protein, displayed skewed ,/, light chain usage consistent with clonal dominance. These observations extend the association between expression of the 1F7 idiotype and abnormal B cell clonal dominance in HIV and SIV infection to HCV infection and suggest that early establishment of an oligoclonal antibody response against HCV may freeze the B cell repertoire, impair adaptation to emergent HCV variants, and favor escape from neutralizing antibodies. We also demonstrated that expression of the 1F7 idiotype extends beyond antibodies against multiple antigens of AIDS-causing retroviruses to include antibodies against multiple antigens of an unrelated chronic hepatitis virus. Thus, distinct pathogens establishing chronic infection in the face of strong humoral immune responses select antibodies along a common idiotypic axis of the immune network. J. Med. Virol. 66:13,21, 2002. © 2002 Wiley-Liss, Inc. [source] Pinpointing a selective sweep to the chimpanzee MHC class I region by comparative genomicsMOLECULAR ECOLOGY, Issue 8 2008NATASJA G. DE GROOT Abstract Chimpanzees experienced a reduction of the allelic repertoire at the major histocompatibility complex (MHC) class I A and B loci, which may have been caused by a retrovirus belonging to the simian immunodeficiency virus (SIV) family. Extended MHC haplotypes were defined in a pedigreed chimpanzee colony. Comparison of genetic variation at microsatellite markers mapping inside and outside the Mhc region was carried out in humans and chimpanzees to investigate the genomic extent of the repertoire reduction. Multilocus demographic analyses underscored that chimpanzees indeed experienced a selective sweep that mainly targeted the chromosomal segment carrying the Mhc class I region. Probably due to genetic linkage, the sweep also affected other polymorphic loci, mapping in the close vicinity of the Mhc class I region genes. Nevertheless, although the allelic repertoire at particular Mhc class I and II loci appears to be limited, naturally occurring recombination events allowed the establishment of haplotype diversity after the sweep. However, recombination did not have sufficient time to erase the signal of the selective sweep. [source] Expression of peripherin in the brain of macaques (Macaca mulatta and Macaca fascicularis) occurs in astrocytes rather than neurones and is associated with encephalitisNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2001J. S. Mathew Peripherin is a member of the type III intermediate filament family, expressed in neurones of the peripheral nervous system of many species and in a discrete subpopulation of neurones of the central nervous system (CNS) during early development in rodents. Previous studies on rats have shown that peripherin immunoreactivity increased significantly in cell bodies of spinal motor neurones following axonal injury. Our study examined the expression of peripherin in the cerebrum of normal macaques (Macaca mulatta and Macaca fascicularis) and those with encephalitis of viral (simian immunodeficiency virus and simian virus 40) or autoimmune (experimental allergic encephalomyelitis) aetiology. Immunohistochemistry, immunoelectronmicroscopy, immunofluorescence and confocal microscopy were performed on tissue sections using antibodies against cell-specific markers and peripherin. Peripherin-positive cells were absent in the cerebrum of normal macaques of all ages examined, whereas animals with encephalitis had peripherin-positive cells associated with inflammatory infiltrates. Further evaluation revealed that these peripherin-positive cells were not neurones, but were predominantly astrocytes expressing glial fibrillary acidic protein. Our study suggests that peripherin is not neurone-specific in the CNS of macaques; peripherin is expressed in astrocytes of animals with encephalitis. [source] Synergistic neuroprotective effect via simian lentiviral vector-mediated simultaneous gene transfer of human pigment epithelium-derived factor and human fibroblast growth factor-2 in rodent models of retinitis pigmentosaTHE JOURNAL OF GENE MEDICINE, Issue 12 2008Masanori Miyazaki Abstract Background We previously demonstrated that a new lentiviral vector derived from nonpathogenic simian immunodeficiency virus (SIVagm) was efficient and safe for long-lasting retinal gene transfer, and that it provided the significant therapeutic effect of expressing human pigment epithelium-derived factor (hPEDF) in Royal College of Surgeons (RCS) rats. In the present study, to obtain a more pronounced outcome, we assessed the potential synergistic effect of the simultaneous gene transfer of hPEDF and human fibroblast growth factor-2 (hFGF-2) by improved third-generation SIV on RCS rats and retinal degeneration slow (rds) mice, because the former targets the primary neurons, including photoreceptor cells (PCs), whereas the latter is effective for targeting secondary neural cells, including Muller cells. Methods Vector solution (SIV-hPEDF, SIV-hFGF-2, a 1 : 1 mixture of SIV-hPEDF and SIV-hFGF-2, or SIV-enhanced green fluorescent protein) was injected into the peripheral subretinal space of 3-week-old RCS rats or rds mice. Histopathological and electroretinographic assessments were made at several points after gene transfer. Results Administration of SIV-hPEDF or SIV-hFGF-2 significantly delayed the histological PC degeneration and electrical deficit in RCS rats, and these delays were synergistically and significantly pronounced by SIV-hPEDF + SIV-hFGF-2 (1 : 1 mixture). In rds mice, functional therapeutic effects were observed even by SIV-PEDF, or SIV-FGF-2 alone and, moreover, both SIV-PEDF and SIV-FGF-2 showed higher therapeutic effects. Conclusions These synergistic rescues of retinitis pigmentosa (RP) model animals are the ,proof concept' that the ,dual' expression of hPEDF and hFGF-2 dramatically improved therapeutic efficacy by keeping lower titers. This strategy may contribute to safer and more effective gene therapy for RP. Copyright © 2008 John Wiley & Sons, Ltd. [source] Development and characterization of a minimal inducible packaging cell line for simian immunodeficiency virus-based lentiviral vectorsTHE JOURNAL OF GENE MEDICINE, Issue 4 2002Seraphin Kuate Abstract Background Lentiviral vectors allow gene transfer into non-dividing cells. Further development of these vector systems requires stable packaging cell lines that enable adequate safety testing. Methods To generate a packaging cell line for vectors based on simian immunodeficiency virus (SIV), expression plasmids were constructed that contain the codon-optimized gag-pol gene of SIV and the gene for the G protein of vesicular stomatitis virus (VSV-G) under the control of an ponasterone-inducible promoter. Stable cell lines expressing these packaging constructs were established and characterized. Results The RT activity and vector titers of cell clones stably transfected with the inducible gag-pol expession plasmid could be induced by ponasterone by more than a factor of 1000. One of these clones was subsequently transfected with the ponasterone-inducible VSV-G expression plasmid to generate packaging cells. Clones of the packaging cells were screened for vector production by infection with an SIV vector and subsequent induction by ponasterone. In the supernatant of selected ponasterone-induced producer clones vector titers of more than 1×105 transducing units/ml were obtained. Producer cell clones were stable for at least five months, as tested by vector production. Conclusions The packaging cells described should be suitable for most preclinical applications of SIV-based vectors. By avoiding regions of high homology between the vector and the packaging constructs, the design of the SIV packaging cell line should reduce the risk of transfer of packaging genes to target cells and at the same time provide flexibility with respect to the SIV vector constructs that can be packaged. Copyright © 2002 John Wiley & Sons, Ltd. [source] HIV and SIV infection: the role of cellular restriction and immune responses in viral replication and pathogenesisAPMIS, Issue 5-6 2009KENNETH C. WILLIAMS The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have a long biological history. Both viruses evolved from Africa and remnants of them can be found in the ,fossil record' of several species in which they are not endemic. SIV remains endemic in several species of monkeys in Africa where it does not cause immune deficiency. HIV and SIV actively replicate within humans and Asian non-human primates, despite cellular and genetic viral restriction factors and genes, and at times robust innate and adaptive immune responses. While Lentiviruses are considered ,slow viruses' it is clear in humans and susceptible Asian monkeys that virus production is rapid and highly active. This results in a massive loss of CD4+ memory effector T cells early after infection and a continued race between viral evolution, cytotoxic lymphocytes, and failed neutralizing antibody responses. Concurrently, HIV and SIV can infect monocyte/macrophage populations in blood and more importantly in tissues, including the central nervous system, where the virus can remain sequestered and not cleared by anti-retroviral therapy, and hide for years. This review will discuss species and cellular barriers to infection, and the role of innate and acquired immunity with infection and pathogenesis of HIV and SIV in select species. [source] Structural improvement of unliganded simian immunodeficiency virus gp120 core by normal-mode-based X-ray crystallographic refinementACTA CRYSTALLOGRAPHICA SECTION D, Issue 4 2009Xiaorui Chen The envelope protein gp120/gp41 of simian and human immunodeficiency viruses plays a critical role in viral entry into host cells. However, the extraordinarily high structural flexibility and heavy glycosylation of the protein have presented enormous difficulties in the pursuit of high-resolution structural investigation of some of its conformational states. An unliganded and fully glycosylated gp120 core structure was recently determined to 4.0,Å resolution. The rather low data-to-parameter ratio limited refinement efforts in the original structure determination. In this work, refinement of this gp120 core structure was carried out using a normal-mode-based refinement method that has been shown in previous studies to be effective in improving models of a supramolecular complex at 3.42,Å resolution and of a membrane protein at 3.2,Å resolution. By using only the first four nonzero lowest-frequency normal modes to construct the anisotropic thermal parameters, combined with manual adjustments and standard positional refinement using REFMAC5, the structural model of the gp120 core was significantly improved in many aspects, including substantial decreases in R factors, better fitting of several flexible regions in electron-density maps, the addition of five new sugar rings at four glycan chains and an excellent correlation of the B -factor distribution with known structural flexibility. These results further underscore the effectiveness of this normal-mode-based method in improving models of protein and nonprotein components in low-resolution X-ray structures. [source] How Oestrogen or Progesterone might Change a woman's susceptibility to HIV-1 infectionAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 5 2002Li Mingjia ABSTRACT Worldwide, 18.5 million women are infected with the human immunodeficiency virus (HIV-1). At least 80% of these HIV infections have occurred as a result of sexual intercourse with an infected male partner. This review focuses on how HIV-1 enters the human female reproductive tract, and how oestrogen or progesterone, by altering the cervicovaginal epithelium, might change a woman's susceptibility to HIV infection. Experiments on hysterectomised Rhesus monkeys suggest that the vagina, rather than the cervix or uterus, is the main site of viral entry. If ovariectomised monkeys are given systemic oestrogen treatment, this makes them completely resistant to infection by intravaginally administered simian immunodeficiency virus (SIV), whereas progesteronetreated animals, like the untreated controls, are extremely susceptible. Some studies have also shown that women on systemic long-acting gestagen-only contraceptives have a thinner vaginal epithelium and hence might be more susceptible to HIV infection; this is certainly true of post-menopausal women. The beneficial effects of oestrogen are thought to be due to increased thickness and cornification of the cervicovaginal epithelium, which prevents the virus from coming into contact with the target Langerhans cells (LCs). Topical vaginal oestrogen treatment is widely used as a safe and effective way of thickening and keratinising the vaginal epithelium in post-menopausal women. Perhaps this could be an exciting new way of protecting women from HIV infection. [source] Expression, purification, crystallization and preliminary X-ray diffraction analysis of rhesus macaque CD8,, homodimerACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2010Lili Zong As a T-cell co-receptor, CD8 binds to MHC class I molecules and plays a pivotal role in the activation of cytotoxic T lymphocytes. To date, structures of CD8 have been solved for two different mammals: human and mouse. The infection of rhesus macaques (Macaca mulatta) by simian immunodeficiency virus (SIV) is the best animal model for studying HIV. In this study, the rhesus macaque CD8 (rCD8) ,, homodimer was obtained and rCD8, exodomain protein crystals were successfully obtained for further structural analysis. Diffraction data were collected to a resolution of 2.4,Å. The crystal belonged to space group P212121, with unit-cell parameters a = 46.52, b = 56.28, c = 82.40,Å. These data will facilitate further studies on the structural differences between these CD8 structures and the cellular immune responses of rhesus macaque. [source] Mother-to-infant transmission of SIV via breast-feeding in rhesus macaquesJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4-5 2003A.M. Amedee Abstract: To decipher the mechanisms involved in oral transmission of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) through breast-feeding, we have developed an animal model using SIV-infected lactating rhesus macaques (Macaca mulatta) and their infants. Five of eight macaque infants became infected during a 10-month study course after SIV inoculation of lactating dams. In a second study, three of four chronically infected female macaques transmitted virus to their infants through breast-feeding within 4 months of birth. Transmission of virus to infants did not correlate with viral loads in either milk or plasma. Infants were infected with homogeneous virus populations, while milk samples near the time of transmission were more diverse. These studies suggest that specific viral phenotypes are selectively transmitted through breast-feeding. [source] | ||||||||||||||||