Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1.

Immunosuppression following infection with HIV-1 predisposes patients to a myriad of opportunistic pathogens, one of the most important of which is Mtb. Granulysin, expressed by NK cells and CTL, exhibits potent antimicrobial activity against Mtb and several other opportunistic pathogens associated with HIV-1 infection. The immune signals that promote granulysin expression in human CTL are not fully understood. Using primary human CD8+ T cells, in this study, we identify IL-21 as a strong inducer of granulysin, demonstrate that IL-21 and IL-15 activate granulysin expression within CD8+ CD45RO+ T cells, and establish a role for Jak/STAT signaling in the regulation of granulysin within CD8+ T cells. We show that infection of PBMC from healthy donors in vitro with HIV-1 suppresses granulysin expression by CD8+ T cells, concomitant with reduced p-STAT3 and p-STAT5, following activation with IL-15 and IL-21. Of note, simultaneous signaling through IL-15 and IL-21 could partially overcome the immunosuppressive effects of HIV-1 on granulysin expression by CD8+ T cells. These results suggest that HIV-1 infection of PBMC may reduce the antimicrobial profile of activated CD8+ T cells by disrupting signaling events that are critical for the induction of granulysin. Understanding the effects of HIV-1 on CD8+ T cell activation is essential to understanding the physiological basis for inadequate cytotoxic lymphocyte activity in HIV+ patients and for informed guidance of cytokine-based therapy to restore T cell function.

Transient or occult HIV infections may occur more frequently than progressive infections: changing the paradigm about HIV persistence.

Evidence of transient HIV infections was found in 8 subjects at high-risk for HIV infection among 47 longitudinally studied over 2-5 (average approximately 3.5) years, whereas only two subjects developed progressive infection. All of these subjects developed serum antibodies (Ab) to conformational epitopes of HIV gp41 (termed "early HIV Ab"), but the 8 transiently infected subjects lost this Ab within 4-18 months, and did not seroconvert to positivity in denatured antigen EIA or Western Blot (WB). However, the two progressively infected subjects eventually seroconverted in the EIA and WB tests within one to two months after the appearance of "early HIV Ab". HIV env and nef sequences were directly PCR amplified from the peripheral blood mononuclear cells (PBMCs) of two of the eight transiently infected subjects during the time of "early HIV Ab"-postivity, and these showed significant sequence divergence from the HIV strains in the laboratory, indicating that they were not laboratory contaminants. Genome identity typing ("paternity-typing") of PBMC samples obtained at the time of "early HIV Ab"-positivity, and later when Ab was absent from each of the 8 subjects, showed that blood samples were not mixed-up. This provides further evidence that transient or occult infection with HIV does occur, and perhaps at a greater frequency than do progressive infections.

Preventing sexual transmission of HIV: anti-HIV bioregulatory and homeostatic components of commercial sexual lubricants.

Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibit both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, we tested five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol). The paraben preservatives and propylene glycol in the lubricants did not inhibit HIV, while the common natural homeostatic metabolite, glycerin, and the thickener polyquaternium-32 did strongly inactivate infectious HIV and HIV-infected leukocytes. Activity against HIV and HIV-infected cells by glycerin was stable through 24 hours at 37 degrees C. Glycerin and polyquaternium-32 were active at minimum concentrations of approximately 2% and 0.01%, respectively--well within the highest FDA safety guidelines. Both active components disrupted infected leukocytes within 5 minutes which resulted in inhibition of infectious HIV production by infected leukocytes of greater than 25 to 100-fold. These components do not disrupt vaginal epithelial cells in vivo. These components also rapidly inactivate cell-free HIV by 10- to 30-fold. Thus, we may conclude that the active components of the OTC lubricants are glycerin and polyquaternium-32. Using these components, OTC sexual lubricants could be reformulated to optimize their anti-HIV activity. Furthermore, clinical trials of these lubricants and components seem to be indicated because of their FDA safety level, wide availability, and low cost.

Practical prevention of vaginal and rectal transmission of HIV by adapting the oral defense: use of commercial lubricants.

HIV is transmitted to 6.4 million human beings per year and the majority of these transmissions are sexual. Condoms are highly effective and are recommended as the primary preventive. However, the fact that there are millions of sexual transmissions each year indicates that many people do not use condoms and that additional preventives are needed. The mechanisms of natural prevention of oral transmission by saliva may be adaptable to the susceptible vagina and rectum. The objective of our study was to reduce the sexual transmission of HIV by mimicking saliva's targeting of the transmitting infected leukocytes and any cell-free HIV in seminal fluid. The previously recommended anti-HIV topical microbicide, nonoxynol-9, has not prevented HIV transmission in humans, probably because it causes mucosal irritation and attracts CD4(+) cells. To identify effective preparations that are nonirritating, we studied the anti-HIV activity of commercially available, over-the-counter (OTC) lubricants and vaginal preparations that are judged safest by the U.S. Food and Drug Administration (FDA), and are nonirritating. The effect of OTC preparations on both the production of HIV by infected leukocytes and cell-free HIV suspended in seminal fluid was measured under simulated in vivo conditions. We surveyed 22 OTC vaginal preparations and excluded those with low inhibitory activity and those that were inhibitory but likely to be irritating. Three included preparations are highly active against both HIV-infected leukocytes suspended in seminal fluid and active against cell-free HIV, under in vitro conditions that simulate in vivo conditions. Since the preparations identified here as anti-HIV substances have the advantages of being widely available, inexpensive, acceptable, in the safest U.S. FDA category, and may be used by recipient women or men, they should be tested in clinical trials to help prevent sexual transmission of HIV.

How does HIV cause depletion of CD4 lymphocytes? A mechanism involving virus signaling through its cellular receptors.

HIV infection causes an acquired immunodeficiency, principally because of depletion of CD4 lymphocytes. The mechanism by which the virus depletes these cells, however, is not clearly understood. Since the virus predominantly infects CD4 lymphocytes in vivo, some have assumed that HIV replication directly kills the infected cells or that the anti-HIV immune response destroys them. However, a large number of studies do not support this concept. Rather, the data strongly indicate that CD4 lymphocyte depletion is by an indirect mechanism. Several theories on various direct and indirect mechanisms are reviewed. The most plausible mechanism, which is backed by in vivo data, involves the consequences of HIV contact with resting CD4 lymphocytes, which cannot support virus replication. HIV binding to, and signaling through, CD4 and chemokine receptor molecules on resting CD4 lymphocytes and other cell types [which extensively occurs as the rare, productively infected cells (ie: infected cells producing virus) migrate among other cells through the lymphoid tissues back into the blood] induces upregulation of L-selectin and Fas. When these resting, HIV-signaled CD4 cells return to the blood, they home very rapidly back to peripheral lymph nodes and axial bone marrow, and their disappearance from the blood is likely due to their leaving the circulatory system. Approximately one-half of these cells that have been induced by HIV to home to lymph nodes are subsequently induced into apoptosis during the process of trans-endothelial migration when secondary signals are received through various homing receptors. These cells are not making HIV, which would explain the observation that CD4 cells not making HIV are the predominant cells dying in the lymph nodes of HIV+ subjects. These studies indicate that the principal mechanism of CD4 T-cell depletion by HIV is due to its use of CD4 as its primary receptor and the signaling induced through this receptor on nonpermissive (resting) T-lymphocytes. This unique mechanism of viral pathogenesis, if correct, leads to the possibility that HIV might not cause depletion of CD4 lymphocytes if it used some other receptor to infect CD4 lymphocytes.

How does HIV cause AIDS? The homing theory.

The mechanism by which HIV causes depletion of CD4+ T cells in infected individuals remains unknown. Numerous theories have been proposed, but none can fully explain all of the events observed to occur in patients. Recent studies have shown that HIV binding to resting CD4+ T cells upregulates L-selectin, causing the cells to home from the blood into lymph nodes at an enhanced rate. It is possible that the disappearance of CD4+ T cells in the blood is actually the result of them leaving the blood, which can help explain the loss of CD4+ T cells in the blood occurring at a much faster rate than in lymphoid tissues. Furthermore, secondary signals through homing receptors received during the homing process induce many of these cells into apoptosis. These cells die in the lymph nodes without producing HIV particles, which can explain the 'bystander effect' observed in the lymph nodes of HIV infected individuals. If this scenario occurs in HIV+ patients, it might explain many of the clinical observations.

The potential importance of HIV-induction of lymphocyte homing to lymph nodes.

The mechanism by which HIV causes depletion of CD4 lymphocytes remains unknown. Recent studies have demonstrated that HIV binding to resting CD4 lymphocytes causes them to home from the blood into lymph node, and during the homing process, they are induced into apoptosis only to secondary signals through the homing receptors. If this is the principal mechanism of CD4 cell depletion, it can explain many of the events known to occur in HIV-infected individual.

Why is HIV rarely transmitted by oral secretions? Saliva can disrupt orally shed, infected leukocytes.

BACKGROUND: Oral transmission of human immunodeficiency virus (HIV) by the millions of HIV-infected individuals is a rare event, even when infected blood and exudate is present. Saliva of viremic individuals usually contains only noninfectious components of HIV indicating virus breakdown. OBJECTIVE: To determine whether unknown HIV inhibitory mechanisms may explain the almost complete absence of infectious HIV in the saliva. METHODS: Since most of the infectious HIV that is shed mucosally by asymptomatic individuals is found in, produced by, and transmitted by infected mononuclear leukocytes, we determined whether saliva, which is hypotonic, may disrupt these infected cells, thereby preventing virus multiplication and cell-to-cell transmission of HIV. Specifically, we measured (1) whether mononuclear leukocytes were lysed by saliva and (2) whether the lysis by saliva inhibits the multiplication of HIV and other viruses in infected leukocytes and other cells. RESULTS: Saliva rapidly disrupted 90% or more of blood mononuclear leukocytes and other cultured cells. Concomitantly, there was a 10000-fold or higher inhibition of the multiplication of HIV and surrogate viruses. Further experiments indicated that the cell disruption is due to the hypotonicity of saliva: CONCLUSIONS: Hypotonic disruption may be a major mechanism by which saliva kills infected mononuclear leukocytes and prevents their attachment to mucosal epithelial cells and production of infectious HIV, thereby preventing transmission. Implications for the known oral HIV transmission by milk and seminal fluid, as well as potential oral transmission to contacts and health care workers, are considered. This effective salivary defense may be applicable medically to interdict vaginal, rectal, and oral transmission of HIV by infected cells in seminal fluid or milk by the use of anticellular substances.

A novel mechanism of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: induction of lymph node homing and apoptosis upon secondary signaling through homing receptors.

Recently, we reported that abortive HIV infection of resting human T lymphocytes up-regulated expression of CD62L, the receptor for homing to lymph nodes (LNs), and enhanced homing of these cells from the blood into the LNs (Wang et al., 1997, Virology 228:141). This suggested that HIV-induced homing of resting lymphocytes (which comprise >98% of all lymphocytes) may be a major mechanism for the reduction of CD4+ lymphocytes in the blood of infected individuals. This mechanism also could be partially responsible for the lymphadenopathy that often develops at the same time that CD4+ lymphocytes are disappearing from the blood. In this study, we show that secondary signaling through the homing receptors (CD62L, CD44, CD11a) of abortively infected resting CD4+ T lymphocytes induced apoptosis. These signals would occur as the cells home into the LNs. Apoptosis did not occur after secondary signaling through some other receptors (CD26, CD4, CD45, and HLA class I) or in HIV-exposed resting CD8+ lymphocytes signaled through the homing receptors. These findings indicate that HIV-induced homing of resting CD4+ lymphocytes to LNs results in death of many of these cells. This was confirmed in the LNs of SCID mice that were i.v. injected with HIV-exposed resting human lymphocytes. Thus, these effects of HIV upon binding to resting CD4+ T lymphocytes, which are not permissive for HIV replication, may significantly contribute to their depletion in vivo. These findings also offer an explanation for the bystander effect observed in the LNs of AIDS patients, whereby cells not making virus are dying.

Occult systemic infection and persistent simian immunodeficiency virus (SIV)-specific CD4(+)-T-cell proliferative responses in rhesus macaques that were transiently viremic after intravaginal inoculation of SIV.

The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenic SIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391-6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55(gag) and/or gp130(env) antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag-specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.

Apoptotic killing of CD4+ T lymphocytes in HIV-1-infected PHA-stimulated PBL cultures is mediated by CD8+ LAK cells.

In vitro infection of PHA-stimulated, normal CD4+ human peripheral blood T lymphocytes (PBLs) with several HIV-1 isolates did not result in cytopathology, despite high levels of virus replication and the fact that some of these isolates were cytopathic in certain cell lines. In contrast, infection of unfractionated PBLs (containing CD8+ as well as CD4+ lymphocytes) with these isolates always resulted in death of the infected CD4+ T lymphocytes. It has been well documented that PHA stimulation and culture of PBLs in medium containing IL-2 generates lymphokine-activated killer (LAK) cell activity which can destroy many transformed cells and virus-infected normal cells. When CD8+ T lymphocytes from PHA-stimulated PBLs were added to HIV-1-infected purified CD4+ T lymphocytes, significant lysis occurred. This cytotoxicity was not MHC class I-restricted, and depletion of CD8+ T lymphocytes from unfractionated PBL cultures shortly after HIV infection largely abolished the killing of the infected CD4+ T lymphocytes. These results demonstrated that CD8+ LAK cells were killing the CD4+ T lymphocytes in unfractionated PBL cultures infected with these noncytopathic HIV-1 strains. Care is thus warranted when studying HIV cytopathology in unfractionated PBL cultures. Morphological and DNA gel electrophoretic analyses of HIV-infected CD4+ T lymphocytes being killed by CD8+ LAK cells demonstrated that apoptosis was the predominant mechanism of LAK cell-mediated killing. In contrast, necrosis was the major mechanism involved in killing of purified CD4+ T lymphocytes by HIV-1 strains which were directly cytopathic. These findings may explain some of the discrepancies in the literature concerning reports of either apoptotic or necrotic killing of cells by HIV in vitro. Moreover, these data strongly suggest that direct killing by replicating HIV-1 in vivo should reveal necrotic cells and immune effector cell killing should reveal apoptotic cells. Since the latter are much more frequently observed in vivo, perhaps immune effector-mediated depletion of CD4+ T lymphocytes is more important as a pathogenic mechanism.

Proteolysis in the myelopathy of acquired immunodeficiency syndrome: preferential loss of the C-8 component of myelin basic protein.

Many patients with AIDS have a myelopathy characterized by vacuolization of spinal cord white matter. The biochemical and molecular changes underlying this myelin disturbance have not yet been characterized. Myelin basic protein (MBP) is potentially important because it is a key structural protein of myelin with roles in compaction and stabilization. In the present study, we describe the steady-state protein concentration of MBP in 46 patients with AIDS and 12 control subjects at autopsy. Patients with myelopathy exhibited no change in the abundance of the predominant 18.5- and 17.2-kd isoforms, but a 14-kd MBP-immunoreactive degradation fragment was increased significantly. MBP degradation correlated significantly with the severity of histopathologic changes, including neutral lipid deposition, the density of vacuolated fibers, and the number of ferritin-stained activated microglia. Alkaline gel electrophoresis of isolated MBP showed preferential loss of the least cationic isomer (C-8). The concentration of MBP RNA in slot blots was normal in cords exhibiting myelopathy, and the ratio of mRNA corresponding to the 18.5- and 17.2-kd MBP isoforms, measured using reverse transcriptase-PCR, was not altered. This study suggests that mononuclear phagocyte-mediated degradation of MBP may play a role in AIDS myelopathy, and the preferential loss of the C-8 component of MBP may have mechanistic implications.

A naturally arising mutation of a potential silencer of exon splicing in human immunodeficiency virus type 1 induces dominant aberrant splicing and arrests virus production.

We have isolated a naturally arising human immunodeficiency type 1 (HIV-1) mutant containing a point mutation within the env gene. The point mutation resulted in complete loss of balanced splicing, with dominant production of aberrant mRNAs. The aberrant RNAs arose via activation of normally cryptic splice sites flanking the mutation within the env terminal exon to create exon 6D, which was subsequently incorporated in aberrant env, tat, rev, and nef mRNAs. Aberrant multiply spliced messages contributed to reduced virus replication as a result of a reduction in wild-type Rev protein. The point mutation within exon 6D activated exon 6D inclusion when the exon and its flanking splice sites were transferred to a heterologous minigene. Introduction of the point mutation into an otherwise wild-type HIV-1 proviral clone resulted in virus that was severely inhibited for replication in T cells and displayed elevated usage of exon 6D. Exon 6D contains a bipartite element similar to that seen in tat exon 3 of HIV-1, consisting of a potential exon splicing silencer (ESS) juxtaposed to a purine-rich sequence similar to known exon splicing enhancers. In the absence of a flanking 5' splice site, the point mutation within the exon 6D ESS-like element strongly activated env splicing, suggesting that the putative ESS plays a natural role in limiting the level of env splicing. We propose, therefore, that exon silencers may be a common element in the HIV-1 genome used to create balanced splicing of multiple products from a single precursor RNA.

Human immunodeficiency virus type 1 Vpu modifies viral cytopathic effect through augmented virus release.

We characterized two human immunodeficiency virus type 1 (HIV-1) strains, HIVMCK and HIV213, which have different cytopathic effects in infected cells. HIV213 was highly cytopathic, whereas HIVMCK was not. Biological analyses of chimeric viruses from the cloned infectious DNAs of HIVMCK and HIV213 showed that the Vpu region was responsible for the differing cytopathicity of these viruses. Although HIVMCK expressed Vpu protein, HIV213 did not because of a mutation at the start codon for Vpu. The amounts of envelope glycoprotein and virus particles associated with the cell surface were significantly increased on cells infected with Vpu-deficient viruses compared with Vpu-positive viruses. These data suggest that the highly cytopathic effects of HIV213 (Vpu-deficient) are due to an accumulation of envelope glycoprotein at the infected-cell surface, which would be caused by the retention of progeny virions in the absence of Vpu-facilitated virion release.

HIV induces homing of resting T lymphocytes to lymph nodes.

In vivo infection with human immunodeficiency virus type 1 (HIV-1) leads to gradual depletion of CD4+ T lymphocytes from the peripheral blood and later from the lymphoid organs. The mechanism of CD4 cell depletion is not known. HIV can only replicate in dividing lymphocytes, but greater than 98% of the lymphocytes in vivo at any given time are resting and are not permissive for productive infection. We found that exposure of resting CD4+ T lymphocytes to HIV-1 transiently upregulated expression of cell surface CD62L (L-selectin), the receptor for homing to lymph nodes, with concomitant enhanced ability of these cells to bind to lymph node high endothelial venules in an ex vivo homing assay (increased approximately 12-fold, P < 0.001) and to home from the blood into lymph nodes following intravenous injection into SCID mice. This suggested the possibility that decreases in numbers of CD4+ T lymphocytes in the blood of HIV-1-infected subjects may reflect enhanced homing of abortively infected, resting lymphocytes into lymph nodes rather than direct virus replication in and killing of these cells, and may explain development of lymphadenopathy at a time when numbers of CD4+ T lymphocytes in the blood fall.

Gradual shutdown of virus production resulting in latency is the norm during the chronic phase of human immunodeficiency virus replication and differential rates and mechanisms of shutdown are determined by viral sequences.

Most CD4+ lymphocytes in lymph nodes of both asymptomatic HIV-1-infected individuals and AIDS patients are nonproductively or latently infected. It is not clear how these cells come about because infection of resting lymphocytes results in abortive infection and infection of activated lymphocytes results in productive infection. The frequency and mechanisms underlying nonproductive or latent HIV infections of normal CD4+ lymphocytes largely remain unexplored, and because HIV latency has principally been studied in latently infected cell clones of established cell lines, it is not even clear how often this type of infection occurs in cell lines. We demonstrate herein that chronic HIV replication in populations of normal phytohemagglutinin-stimulated peripheral blood CD4(+)-enriched lymphocytes, as well as an established T-cell line (CEM), gradually shuts down in the vast majority of cells. The nonproducing cells in these cultures still harbored HIV provirus, and HIV could be reactivated in CEM cells by treatment with phorbol ester, showing that this was latent infection. Thus, HIV's life cycle should probably be considered as consisting of two phases an acute exponential rise in production of virus progeny which levels at some peak, followed by a gradual decline of progeny production during the chronic phase leading to viral latency. Temporal analyses of the steady-state levels of viral mRNAs in populations of chronically infected CEM cells as virus production declined revealed the two mechanisms of HIV latency which have previously been described in the OM-10.1 and U1 or ACH-2 latently infected cell clones (i.e., apparent overall shutdown of HIV transcription and "blocked early-stage latency" involving enhanced splicing of viral pre-mRNAs) However, which mechanism was employed, as well as the rate of shutdown, depended on the virus strain.

Rates of shutdown of HIV-1 into latency: roles of the LTR and tat/rev/vpu gene region.

CEM T-cells chronically infected with most HIV-1 isolates gradually cease virus production over a 4-6 week period. This is due to slow shutdown of virus replication in the majority of the cells, leading to latent infections. We identified one HIV-1 isolate (HIV213) which shut down into latency at a rate much slower than most HIV strains, requiring more than 12 weeks for the majority of the cells to become nonproductive. This indicated that genes of the virus influence the rate of shutting down, or alternatively, the length of time chronically infected cells produce virus. The viral gene(s) influencing differential rates of shutdown were mapped using chimeric viruses composed of the HIV213 genome substituted with various restriction fragments from HIV(MCK), which rapidly progresses into latency. We found that the 3' region of the LTR was the major determinant influencing the rate of shutdown, but the tat/rev/vpu region also slightly influenced this phenotype. These data show that at least these two genomic regions can influence the duration of virus production in chronically infected cells and that polymorphisms in these regions result in phenotypically divergent viruses which go into latency at different rates. It is also possible that this viral property may be an important determinant of clinical outcomes.

Development of T-cell lines expressing functional HIV-1 envelope glycoproteins for evaluation of immune responses in HIV-infected individuals.

The human T-lymphoid cell line, CEM, was transfected with gp 160 cDNA of human immunodeficiency virus type 1 (HIV-1)pm213. Three clones expressing the envelope glycoproteins (env), designated CEM-213env1, -env4, and -env7, were isolated. These clones expressed high levels of surface gp41 and gp120, as demonstrated by flow cytometry with anti-HIV env monoclonal antibodies. Processing and function of env was shown by induction of syncytia with CD4-expressing HeLa cells and by immunoblot analysis. The env expression resulted in specific down-regulation of surface CD4 levels, supporting the role of HIV env in CD4 modulation. Furthermore, serum samples from nine of nine HIV-1-infected individuals bound specifically to the env-expressing transfectants, substantiating the presence of conserved antigenic determinants. These sera also mediated antibody-dependent cellular cytotoxicity (ADCC) of the env-expressing cell lines. The env-expressing cell lines provide a relevant, safe, and practical model for qualitative and quantitative analysis of humoral and cellular immune responses and their role in HIV-1 pathogenesis and therapy.

Expansion of the cerebral ventricles and correlation with acquired immunodeficiency syndrome neuropathology in 232 patients.

BACKGROUND: Expansion of the cerebral ventricles is highly prevalent in patients with the acquired immunodeficiency syndrome (AIDS). The mechanism remains unclear. The purpose of this study was to correlate the volume of the cerebral ventricles with histopathologic abnormalities in the brain. METHODS: At autopsy, the volume of the cerebral ventricles in brain slices was estimated planimetrically in 232 patients with AIDS and 77 age-appropriate controls. Estimated volumes were compared with the neuropathologic results using multiple regression analysis. RESULTS: Multiple regression analysis demonstrated a significant relationship between ventricular volume and cerebral cytomegalovirus infection (P < .0004). When human immunodeficiency virus (HIV) encephalitis with multinucleated cells was present, median volume did not differ significantly from other subjects with AIDS. In 11 patients who had HIV-1 proviral DNA detected using the polymerase chain reaction, average volume was not different from 22 patients who tested negatively using polymerase chain reaction. Ventricular expansion did not have a clear-cut neuropathologic substrate in many instances. CONCLUSIONS: In some subjects with AIDS, cytomegalovirus encephalitis was the underlying neuropathologic lesion associated with ventricular expansion. Key indicators of brain HIV-1 infection were related either weakly or not at all, and the role of HIV-1 remains uncertain in most cases.