Biomedical subjects

B Hurtrel

Publications and source records attributed to B Hurtrel.

At least 19 recordsLinked to original sources

PubMed2005

Apoptosis in SIV infection.

Pathogenic human immunodeficiency virus (HIV)/Simian immunodeficiency virus (SIV) infection is associated with increased T-cell apoptosis. In marked contrast to HIV infection in humans and SIV infection in macaques, the SIV infection of natural host species is typically nonpathogenic despite high levels of viral replication. In these nonpathogenic primate models, no observation of T-cell apoptosis was observed, suggesting that either SIV is less capable of directly inducing apoptosis in natural hosts (likely as a result of coevolution/coadaptation with the host) or, alternatively, that the indirect T-cell apoptosis plays the key role in determining the HIV-associated T-cell depletion and progression to acquired immune deficiency syndrome (AIDS). Understanding the molecular and cellular mechanisms responsible for the disease-free equilibrium in natural hosts for SIV infection, including those determining the absence of high levels of T-cell apoptosis, is likely to provide important clues regarding the mechanisms of AIDS pathogenesis in humans.

Animals↗

PubMed2004

Viral load in tissues during the early and chronic phase of non-pathogenic SIVagm infection.

African green monkeys (AGMs) persistently infected with SIVagm do not develop AIDS, although their plasma viremia levels can reach those reported for pathogenic HIV-1 and SIVmac infections. In contrast, the viral burden in lymph nodes in SIVagm-infected AGMs is generally lower in comparison with HIV/SIVmac pathogenic infections, at least during the chronic phase of SIVagm infection. We searched for the primary targets of viral replication, which might account for the high viremias in SIVagm-infected AGMs. We evaluated for the first time during primary infection SIVagm dissemination in various lymphoid and non-lymphoid tissues. Sixteen distinct organs at a time point corresponding to maximal virus production were analyzed for viral RNA and DNA load. At days 8 and 9 p.i., viral RNA could be detected in a wide range of tissues, such as jejunum, spleen, mesenteric lymph nodes, thymus and lung. Quantification of viral DNA and RNA as well as of productively infected cells revealed that viral replication during this early phase takes place mainly in secondary lymphoid organs and in the gut (5 x 10(4)-5 x 10(8) RNA copies/10(6) cells). By 4 years p.i., RNA copy numbers were below detection level in thymus and lung. Secondary lymphoid organs displayed 6 x 10(2)-2 x 10(6) RNA copies/10(6) cells, while some tissue fragments of ileum and jejunum still showed high viral loads (up to 10(9) copies/10(6) cells). Altogether, these results indicate a rapid dissemination of SIVagm into lymphoid tissues, including the small intestine. The latter, despite showing marked regional variations, most likely contributes significantly to the high levels of viremia observed during SIVagm infection.

Animals↗

PubMed2003

Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression.

Studies of human immunodeficiency virus (HIV) and nonhuman primate models of pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections have suggested that enhanced ex vivo CD4 T-cell death is a feature of pathogenic infection in vivo. However, the relative contributions of the extrinsic and intrinsic pathways to programmed T-cell death in SIV infection have not been studied. We report here that the spontaneous death rate of CD4+ T cells from pathogenic SIVmac251-infected rhesus macaques ex vivo is correlated with CD4 T-cell depletion and plasma viral load in vivo. CD4+ T cells from SIVmac251-infected macaques showed upregulation of the death ligand (CD95L) and of the proapoptotic proteins Bim and Bak, but not of Bax. Both CD4+ and CD8+ T cells from SIVmac251-infected macaques underwent caspase-dependent death following CD95 ligation. The spontaneous death of CD4+ and CD8+ T cells was not prevented by a decoy CD95 receptor or by a broad-spectrum caspase inhibitor (zVAD-fmk), suggesting that this form of cell death is independent of CD95/CD95L interaction and caspase activation. IL-2 and IL-15 prevented the spontaneous death of CD4+ and CD8+ T cells, whereas IL-10 prevented only CD8 T-cell death and IL-7 had no effect on T-cell death. Our results indicate that caspase-dependent and caspase-independent pathways are involved in the death of T cells in pathogenic SIVmac251-infected primates.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Distinct cycling CD4(+)- and CD8(+)-T-cell profiles during the asymptomatic phase of simian immunodeficiency virus SIVmac251 infection in rhesus macaques.

Elevated CD4 T-cell turnover may lead to the exhaustion of the immune system during human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) infections. However, this hypothesis remains controversial. Most studies of this subject have concerned the blood, and information about the lymph nodes is rare and controversial. We used Ki67 expression to measure cycling T cells in the blood and lymph nodes of uninfected macaques and of macaques infected with a pathogenic SIVmac251 strain or with a nonpathogenic SIVmac251Deltanef clone. During the asymptomatic phase of infection, the number of cycling CD8(+) T cells progressively increased (two- to eightfold) both in the blood and in the lymph nodes of macaques infected with SIVmac251. This increase was correlated with viral replication and the progression to AIDS. In contrast, no increases in the numbers of cycling CD4(+) T cells were found in the blood or lymph nodes of macaques infected with the pathogenic SIVmac251 strain in comparison with SIVmac251Deltanef-infected or healthy macaques during this chronic phase. However, the lymph nodes of pre-AIDS stage SIVmac251-infected macaques contained more cycling CD4(+) T cells (low baseline CD4(+)-T-cell counts in the blood). Taken together, these results show that the profiles of CD4(+)- and CD8(+)-T-cell dynamics are distinct both in the lymph nodes and blood and suggest that higher CD4(+)-T-cell proliferation at the onset of AIDS may lead to the exhaustion of the immune system.

Animals↗

PubMed2001

The infiltration kinetics of simian immunodeficiency virus-specific T cells drawn to sites of high antigenic stimulation determines local in vivo viral escape.

Despite vigorous cell-mediated immune responses to human and simian immunodeficiency viruses (HIV/SIV) the immune system is unable to clear latently infected resting T cells. These infected cells are reactivated by antigenic stimulation, leading to viral replication. By using the SIV/macaque model of HIV pathogenesis, the dynamics of T cell infiltration into delayed type hypersensitivity sites specific for the purified protein derivative of bacillus Calmette-Guérin have been studied. Early viral mRNA synthesis coincided with the infiltration of antigen-specific T cells. When the infiltration of anti-SIV-specific T cells was rapid compared with the kinetics of viral assembly, the sites were sterilized before the transition to late viral mRNA synthesis occurred. When their infiltration was slow, ephemeral foci of replication were identified. These findings were paralleled by plasma viremia; low viremia coincided with rapid sterilization of the delayed type hypersensitivity sites, whereas high load was found in association with local replication and delayed sterilization. These data suggest that although effective local control of SIV is possible once antiviral T lymphocytes have arrived on site, the slower deployment of these T cells may allow the virus to escape and thus to reseed the pool of memory T cells.

Animals↗

PubMed2001

Persistence of pathogenic challenge virus in macaques protected by simian immunodeficiency virus SIVmacDeltanef.

Live attenuated simian immunodeficiency virus (SIV) is the most efficient vaccine yet developed in monkey models of human immunodeficiency virus infection. In all successful vaccine trials, attenuation was achieved by inactivating at least the nef gene. We investigated some virological and immunological characteristics of five rhesus macaques immunized with a nef-inactivated SIVmac251 molecular clone (SIVmac251Deltanef) and challenged 15 months later with the pathogenic SIVmac251 isolate. Three animals were killed 2 weeks postchallenge (p.c.) to search for the challenge virus and to assess immunological changes in various organs. The other two animals have been monitored up for 7 years p.c., with clinical and nef gene changes being noted. The animals killed showed no increase in viral load and no sign of a secondary immune response, although the challenged virus was occasionally detected by PCR. In one of the monkeys being monitored, the vaccine virus persisted and an additional deletion occurred in nef. In the other monkey that was monitored, the challenge and the vaccine (Deltanef) viruses were both detected by PCR until a virus with a hybrid nef allele was isolated 48 months p.c. This nef hybrid encodes a 245-amino-acid protein. Thus, our results show (i) that monkeys were not totally protected against homologous virus challenge but controlled the challenge very efficiently in the absence of a secondary immune response, and (ii) that the challenge and vaccine viruses may persist in a replication-competent form for long periods after the challenge, possibly resulting in recombination between the two viruses.

Animals↗

PubMed2000

Generation of CD8+ T cell-generated suppressor factor and beta-chemokines by targeted iliac lymph node immunization in rhesus monkeys challenged with SHIV-89.6P by the rectal route.

The targeted lymph node (TLN) immunization strategy was investigated in macaques, in order to determine the efficacy in generating secretory, systemic, and cellular immune responses, CD8+ T cell-generated suppressor factors, and beta-chemokines. TLN immunization of the rectal and genital mucosa-associated iliac lymph nodes (TILNs) was compared with axillary TLN immunization (TAxLN) using HIV-1 MN/LAI gp140env and SIV p27gag in alum. Significantly higher immune responses, as well as CD8+ T cell-generated anti-SIV factors and the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta, were elicited by iliac as compared with axillary TLN immunization. The immune responses induced by TLN immunization were examined for their capacity to prevent rectal mucosal infection by the pathogenic dual-tropic SHIV-89.6P. Despite significant secretory, serum, cellular, and beta-chemokine responses, the macaques were infected by SHIV-89.6P. Whether the lack of protection was associated with the antigenic unrelatedness of SHIV-89.6P to the immunizing HIV-1 MN/LAI gp140 or to the virus utilizing CXCR4 to a much greater extent than CCR5, remains to be determined.

Animals↗

PubMed2000

Implication of the C-terminal domain of nef protein in the reversion to pathogenicity of attenuated SIVmacBK28-41 in macaques.

We have analyzed the nef gene sequences amplified from 12 macaques presenting various patterns of infection with SIVmacBK28-41, a clone derived from attenuated SIVmacBK28. We have observed seven mutation hot spots at positions 56, 75, 432, 588, 680, 699, and 779. The major alteration was a thymidine insertion at position 699, leading to a frameshift in the SIVmacBK28-41 nef gene and changing the last 15 amino acids of Nef into a 31-amino-acid-long C-terminal domain nearly identical to that encoded by pathogenic SIVmac239 and SIVmac251. The insertion was found at early time points in proviruses obtained from rapid progressor macaques, after 2 years postinfection in progressors, and rarely or only after 4 years postinfection in nonprogressors. Fixation of the other mutations occurred only after insertion of thymidine 699. Phylogenetic analysis demonstrated that the nef genes isolated from progressors evolved from the allele present in SIVmacBK28-41 to alleles present in SIVmac239 or SIVmac251, whereas nef sequences from nonprogressors stayed clustered with that of the inoculated molecular clone. These data stress the importance of the C-terminal extremity of the Nef protein of SIVmac239 or SIVmac251 in viral pathogenesis.

Amino Acid Sequence↗

PubMed2000

Progressive multifocal leukoencephalopathy and oligodendroglioma in a monkey co-infected by simian immunodeficiency virus and simian virus 40.

A rhesus monkey experimentally inoculated with simian immunodeficiency virus (SIV) mac251 was killed 42 months later because of poor general condition. CD4 lymphocyte count which was 3,430/mm3 before inoculation, had decreased to 638/mm3 2 months before death. Neuropathological examination revealed changes characteristic of progressive multifocal leukoencephalopathy (PML) in the white matter of the cerebral hemispheres and brain stem. In situ hybridization was negative for JC virus but markedly positive for simian virus 40 (SV40) in the nuclei of many oligodendrocytes. Many oligodendrocytes also expressed p53. Within an area involved by PML, there was a densely cellular tumor with honeycomb appearance and elongated vessels characteristic of oligodendrogliomas. Within the tumor in situ hybridization for SV40 and immunocytochemistry for p53 were negative. Opportunistic infection by SV40 has been occasionally reported in experimentally SIV-infected monkeys resulting in PML or malignant astrocytoma. Association of JC virus-induced PML and astrocytomas has been reported in three human cases without AIDS. In those cases, as in our monkey, polyomaviruses (SV40 or JC virus) were expressed in the areas with PML but not in the glial tumor. Association of PML and oligodendroglioma has not been reported previously to our knowledge. The relationship between oligodendrocyte proliferation and polyomavirus infection of oligodendrocytes is unclear. Our findings suggest that binding of the viral protein to p53 may result in inactivation of the pro-apoptotic protein favoring the proliferation of a randomly occurring tumoral clone of oligodendrocytes.

Animals↗

PubMed2000

Early changes in peripheral blood T cells during primary infection of rhesus macaques with a pathogenic SIV.

Primary infection of rhesus macaques with pathogenic strains of simian immunodeficiency virus (SIV) leads to rapid and dynamic changes in both viral load and T cell counts in the peripheral blood. We have performed a sequential analysis of peripheral blood CD4 and CD8 T cells in five macaques during the 8 weeks following SIVmac251 infection. We observed a transient lymphopenia of both CD4 and CD8 T cells during the first 2 weeks, followed by a rebound. The primary phase of infection was associated with changes in the T cells expressing CD25, CD69, or HLA-DR and with a priming of the peripheral blood CD4 and CD8 T cells for a process of apoptosis in vitro that was enhanced by CD95 (Fas) ligation, and was detected in two macaques as early as 7 days after infection. Despite the small numbers of animals studied, the importance of the early transient CD4 and CD8 T lymphopenia was positively correlated with the viral load. No correlation was found, however, between the level of activation markers expressed or of priming for apoptosis in peripheral blood T cells and the viral load. Our findings suggest the possibility that the early activation and priming for apoptosis of CD4 and CD8 T cells may involve indirect, host-related, mechanisms, or alternatively, that the T cells that remain in the peripheral blood during primary infection do not adequately reflect the viral-mediated changes in T cell activation and death that may occur in the lymphoid organs throughout the body.

Animals↗

PubMed2000

DNA vaccine protection against challenge with simian/human immunodeficiency virus 89.6 in rhesus macaques.

Twelve Rhesus macaques were immunized by intramuscular injection of naked DNA encoding the SlVmac gag and nef genes, HIV-1 89.6 env and rev genes and the simian interleukin-12 (IL-12) gene. Six of the animals also received two intramuscular injections of gp140 89.6 formulated in QS21. The monkeys were challenged by the intrarectal route, in parallel with six control monkeys, using 750 TCID50 of SHIV-89.6. Virus recovery in PBMC by co-cultivation was as follows: controls: six out of six; DNA only: five out of six; DNA + protein: two out of six. The five animals that remained virus free after this first challenge were challenged a second time, again by the intrarectal route and in parallel with four naive controls, using 600 TCID50 of pathogenic SHIV-89.6P. A rapid CD4 cell count decline was observed in the four control monkeys as well as in the monkey vaccinated with DNA only, but in none of the four animals immunized with DNA + protein. No virus was recovered from PBMC in two of these monkeys, and viral RNA loads in plasma were greatly reduced in three of them as compared with the controls. Absence of virus in PBMC was ascertained by whole blood transfusion to naive recipients. Altogether, this shows that the DNA prime-protein boost vaccine regimen could provide some protection against mucosal SHIV infection in rhesus monkeys, whereas DNA alone was ineffective.

AIDS Vaccines↗

PubMed1999

Viral load and neuropathology in the SIV model.

To investigate neuropathological processes involved in HIV infection, a longitudinal analysis of central nervous system (CNS) changes was performed using the SIV-infected macaque model. Five animals were studied during the early phase and 13 during the asymptomatic and symptomatic phases. Histopathological analyses were performed on one cerebral fixed hemisphere whereas on the other frozen hemisphere in situ hybridisation, immunohistochemistry and RT-PCR were performed. Viral load was quantified by in situ hybridisation, CD4 and CD8 T cell infiltration by immunohistochemistry and mRNA cytokine expression (IL1beta, IL2, IL6, TNFalpha, IFNgamma and TGF-beta1) by semiquantitative RT-PCR. As reported for HIV-infected humans, the neuropathological analysis of SIV infected animals revealed four distinct lesion profiles: minimal changes, early encephalitis, leukoencephalopathy and encephalitis. No relationship was found between neuropathological findings, numbers of SIV replicating cells and T cell infiltration. CNS infection was found to be an early event characterised by glial activation, an increase in the level of IL1beta, TNFalpha and IL6 mRNA expression. During the asymptomatic and symptomatic phases, IL6 and IL1beta mRNAs increase coincided with gliosis and the development of myelin lesions. The absence of relationship between neuropathological findings and viral load suggests that cerebral lesions are caused by an indirect mechanism. Inflammatory cytokine pattern associated with severe lesions show the key role of glial activation in the SIV neuropathological process.

AIDS Dementia Complex↗

PubMed1997

Protection of SIVmac-infected macaque monkeys against superinfection by a simian immunodeficiency virus expressing envelope glycoproteins of HIV type 1.

The infection of macaque monkeys by attenuated simian immunodeficiency virus can vaccinate against pathogenic molecular clones and isolates of the same virus. The correlates of this potent protective immunity are not fully understood but may be the key to an effective AIDS vaccine for humans. Aiming to determine whether host immune responses to envelope glycoprotein are an essential component of the immunity to primate lentiviruses, we have tried to superinfect SIVmac-infected macaque monkeys with SHIVsbg, a chimeric primate lentivirus constructed from the SIVmac239 genome with the env, rev, tat, and vpu genes from HIV-1 Lai. After inoculation of a large dose of SHIVsbg, the chimeric virus was isolated by coculture of mononuclear blood cells from four of five SIV-infected monkeys, but three animals were protected from extracellular SHIV viremia and did not seroconvert to HIV-1 glycoproteins. In the two SIV-infected monkeys that did develop SHIV viremia, cell-associated viral load was reduced at least 100-fold. These data indicate that an antiviral response capable of effectively controlling primate lentivirus replication might not necessarily involve the envelope glycoprotein.

AIDS Vaccines↗

PubMed1997

[Contribution of animal models in the understanding of AIDS encephalopathy].

The neuropathology associated with HIV (Human Immunodeficiency Virus) infection is one of the major complications of this disease. The virological and cellular mechanisms by which HIV infection induces motor and cognitive disorders remain unknown. This lack of understanding of the pathophysiology is partly due to the difficulty of experimental analysis in man because only post-mortem samples from terminal phases of the disease and cerebrospinal fluid samples are available. Two animal models, very closely resembling human HIV infection, are available: the cat model infected by FIV (Feline Immunodeficiency Virus) and the macaque model infected by the SIVmac (Simian Immunodeficiency Virus) which have enabled us to conduct a longitudinal study of encephalopathy during primo-infection and the asymptomatic and pre-AIDS (Acquired Immune Deficiency Syndrome) phases. In the cat-FIV model, which presents the advantage of being non-infectious to man, and therefore easier to manipulate, it was shown that infected cats develop behavioural abnormalities and a neuropathology which resemble HIV dementia. Central nervous system lesions induced by FIV are similar to those of HIV infection apart from the absence of multinucleated giant cells. This model was used to analyse the relationship between CNS lesions and the viral load of the brain and showed that the severity of the lesions contrasted with a low viral load. The pathophysiology of SIVmac infection in the rhesus macaque is almost identical to human infection with a more rapid course, since the duration of the asymptomatic phase is 6 months to 5 years, depending on the animal. We studied the relationship between lesions, viral load and cytokine production (IL-1 beta, IL-2, IL-6, TNF alpha, INF gamma, TGF-beta 1) within the CNS. Our results show early, low-grade and constant infection of the brain. The dissociation between the viral load and the lesions observed is our favour of an indirect mechanism for the pathogenesis of these lesions. The relationship between lesions and the cytokine profile studied shows the importance of glial cells in the pathogenesis of the lesions.

AIDS Dementia Complex↗

PubMed1996

The relationship between the interferon alpha response and viral burden in primary SIV infection.

The interferon alpha (IFN-alpha) response of rhesus macaques was investigated during primary infection with pathogenic and attenuated simian immunodeficiency virus (SIV). IFN-alpha was detected in the serum of animals as early as day 4 after inoculation of SIVmac251, but remained barely detected in animals infected with the attenuated virus SIVmac251 delta nef. The peak of IFN-alpha secretion preceded that of antigenemia in animals infected with pathogenic virus, indicating that the IFN-alpha response did not prevent viral spread. In addition, elevated levels of IFN-alpha in the serum after the acute stage of infection was associated with persisting antigenemia. The analysis of lymph nodes (LNs) by in situ hybridization showed that, similar to the results obtained with peripheral blood, the induction of IFN-alpha in lymphoid organs was rapidly detected in animals infected with the pathogenic virus, but remained very limited in animals infected with the attenuated virus. Quantitation of the hybridization signal indicated that IFN-alpha-producing cells were numerous in the LNs of animals that had a high viral burden. Taken together, these findings indicate that the IFN-alpha response is unable to contain the initial burst of SIV replication.

Animals↗

PubMed1996

Interferon-gamma expression in macaque lymph nodes during primary infection with simian immunodeficiency virus.

Simian immunodeficiency virus (SIV) replication is rapidly downregulated in the lymph nodes (LN) of rhesus macaques after the acute stage of primary infection. The aim of this study was to evaluate a possible role of interferon-gamma (IFN-gamma) in the control of SIV replication. IFN-gamma expression was analysed by in situ hybridization in the LN of rhesus macaques that were inoculated either with a high dose or with a low dose of the pathogenic isolate SIVmac 251. The kinetics of IFN-gamma induction in LN was found to follow that of SIV replication. However, the number of IFN-gamma expressing cells was not proportional to the number of infected cells. IFN-gamma expression in LN was further quantified by competitive RT-PCR. The number of IFN-gamma mRNA molecules in LN was high for the animals of the high dose group. In the low dose group, the IFN-gamma copy number varied over 2 log10 units and was particularly low for the animals that had a high and persisting antigenaemia. The analysis of a total of 10 animals inoculated with a low dose of virus showed an inverse correlation between IFN-gamma expression in LN and peak antigenemia (P < 0.01). This study provides evidence for a marked individual variability in the IFN-gamma response to primary SIV infection and supports the notion that IFN-gamma production is inhibited at an early stage in animals that harbour a high viral load.

Animals↗

PubMed1996

Neuropathology of early HIV-1 infection.

Early HIV-1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV-1 carriers remain neurologically unimpaired during the so called "asymptomatic" period lasting from seroconversion to symptomatic AIDS. Therefore, neuropathological studies in the early pre-AIDS stages are very few, and the natural history of central nervous system changes in HIV-1 infection remains poorly understood. Examination of brains of asymptomatic HIV-1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV-1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T-cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also interfere. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV-1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV-1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV-1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV-1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T-lymphocytes, continuously inhibits viral replication at that stage.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Virus load and neuropathology in the FIV model.

The FIV (feline immunodeficiency virus) induces in cats brain changes presenting similarities with those observed in human immunodeficiency virus infection. This FIV model was used to study the relationship between viral load in brain, in lymphoid organs and central nervous system (CNS) changes during the early and late stages of infection. Early brain changes were analyzed in animals experimentally infected with two different FIV isolates and sacrificed at 7 and 15 days, 1, 2, 6, and 12 months post inoculation (p.i.). Late CNS abnormalities were analyzed in naturally FIV-infected cats referred to the Veterinary School of Nantes. For each animal, one cerebral hemisphere was fixed and examined using routine techniques. The characterization of FIV replicating cells by in situ hybridization was performed on the other half frozen hemisphere on sections performed in the anterior and the median regions of the brain. During the early stages of infection, moderate gliosis with glial nodules and sometimes white matter pallor and meningitis were associated with few infected cells scattered in the brain. Infection was an early event as infected cells could be detected in brain at 7 p.i. For each cat, these findings were found identical in the two analyzed areas. During the late stages, brain lesions and the number of virus replicating cells increased especially in animals with perivascular infiltrates. The multinucleated giant cells encephalitis was never observed and the number of FIV replicating cells scattered in the whole brain was always low. This discrepancy between the number of replicating cells and the brain lesions, corroborates the hypotheses suggesting that brain injuries may be mediated via diffusive factors and amplification processes through cytokine cascades and cell activations.

Animals↗