Jupiter's atmospheric jet streams extend thousands of kilometres deep.

The depth to which Jupiter's observed east-west jet streams extend has been a long-standing question. Resolving this puzzle has been a primary goal for the Juno spacecraft, which has been in orbit around the gas giant since July 2016. Juno's gravitational measurements have revealed that Jupiter's gravitational field is north-south asymmetric, which is a signature of the planet's atmospheric and interior flows. Here we report that the measured odd gravitational harmonics J3, J5, J7 and J9 indicate that the observed jet streams, as they appear at the cloud level, extend down to depths of thousands of kilometres beneath the cloud level, probably to the region of magnetic dissipation at a depth of about 3,000 kilometres. By inverting the measured gravity values into a wind field, we calculate the most likely vertical profile of the deep atmospheric and interior flow, and the latitudinal dependence of its depth. Furthermore, the even gravity harmonics J8 and J10 resulting from this flow profile also match the measurements, when taking into account the contribution of the interior structure. These results indicate that the mass of the dynamical atmosphere is about one per cent of Jupiter's total mass.

A suppression of differential rotation in Jupiter's deep interior.

Jupiter's atmosphere is rotating differentially, with zones and belts rotating at speeds that differ by up to 100 metres per second. Whether this is also true of the gas giant's interior has been unknown, limiting our ability to probe the structure and composition of the planet. The discovery by the Juno spacecraft that Jupiter's gravity field is north-south asymmetric and the determination of its non-zero odd gravitational harmonics J3, J5, J7 and J9 demonstrates that the observed zonal cloud flow must persist to a depth of about 3,000 kilometres from the cloud tops. Here we report an analysis of Jupiter's even gravitational harmonics J4, J6, J8 and J10 as observed by Juno and compared to the predictions of interior models. We find that the deep interior of the planet rotates nearly as a rigid body, with differential rotation decreasing by at least an order of magnitude compared to the atmosphere. Moreover, we find that the atmospheric zonal flow extends to more than 2,000 kilometres and to less than 3,500 kilometres, making it fully consistent with the constraints obtained independently from the odd gravitational harmonics. This depth corresponds to the point at which the electric conductivity becomes large and magnetic drag should suppress differential rotation. Given that electric conductivity is dependent on planetary mass, we expect the outer, differentially rotating region to be at least three times deeper in Saturn and to be shallower in massive giant planets and brown dwarfs.

HIV infection and specific mucosal immunity: workshop 4B.

Most HIV infections are transmitted across mucosal epithelium. An area of fundamental importance is understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, which leads to increased susceptibility to bacterial, fungal, and viral infections of oral and other mucosae. This workshop attempted to address 5 basic issues-namely, HIV acquisition across mucosal surfaces, innate and adaptive immunity in HIV resistance, antiviral activity of breast milk as a model mucosal fluid, neutralizing immunoglobulin A antibodies against HIV, and progress toward a mucosal vaccine against HIV. The workshop attendants agreed that progress had been made in each area covered, with much recent information. However, these advances revealed how little work had been performed on stratified squamous epithelium compared with columnar epithelium, and the attendants identified several important biological questions that had not been addressed. It is increasingly clear that innate immunity has an important biological role, although basic understanding of the mechanisms of normal homeostasis is still being investigated. Application of the emerging knowledge was lacking with regard to homeostatic mucosal immunity to HIV and its role in changing this homeostasis. With regard to breast milk, a series of studies have demonstrated the differences between transmitters and nontransmitters, although whether these findings could be generalized to other secretions such as saliva was less clear. Important progress toward an oral mucosal HIV vaccine has been made, demonstrating proof of principle for administering vaccine candidates into oral lymphoid tissues to trigger anti-HIV local and systemic immune responses. Similarly, experimental data emphasized the central role of neutralizing antibodies to prevent HIV infection via mucosal routes.

Intestinal macrophages and response to microbial encroachment.

Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body. In order to maintain mucosal homeostasis, resident intestinal macrophages uniquely do not express the lipopolysaccharide (LPS) co-receptor CD14 or the IgA (CD89) and IgG (CD16, 32, and 64) receptors, yet prominently display Toll-like receptors (TLRs) 3-9. Remarkably, intestinal macrophages also do not produce proinflammatory cytokines in response to TLR ligands, likely because of extracellular matrix (stromal) transforming growth factor-ß (TGF-ß) dysregulation of nuclear factor (NF)-κB signal proteins and, via Smad signaling, expression of IκBα, thereby inhibiting NF-κB-mediated activities. Thus, in noninflamed mucosa, resident macrophages are inflammation anergic but retain avid scavenger and host defense function, an ideal profile for macrophages in close proximity to gut microbiota. In the event of impaired epithelial integrity during intestinal infection or inflammation, however, blood monocytes also accumulate in the lamina propria and actively pursue invading microorganisms through uptake and degradation of the organism and release of inflammatory mediators. Consequently, resident intestinal macrophages are inflammation adverse, but when the need arises, they receive assistance from newly recruited circulating monocytes.

The effect of secretory leukocyte protease inhibitor (SLPI) on ischemia/reperfusion injury in cardiac transplantation.

We investigated the role of secretory leukocyte protease inhibitor (SLPI) in ischemia/reperfusion injury in cardiac transplantation. SLPI-/- mouse hearts and wild-type (WT) controls were transplanted immediately or after 10 h of cold ischemia (CI). Recombinant SLPI (rSLPI) was added to the preservation solution or given systemically. After evaluation of myocardial performance, grafts were investigated for histology, SLPI, TNF-alpha, TGF-beta, NF-kappaB and protease expression at indicated time points. Early myocardial contraction was profoundly impaired in SLPI-/- hearts exposed to CI and associated with high intra-graft protease expression. Systemic administration of rSLPI had no effect, however, when SLPI was added to the preservation solution, myocardial contraction was restored to normal. At 10 days, inflammation, myocyte vacuolization and necrosis were significantly more severe in SLPI-/- hearts. SLPI gene expression was detected in WT mice at 12 and 24 h and was significantly higher after CI. SLPI protein was observed at 24 h and 10 days. High intra-graft concentrations of SLPI after administration of rSLPI were inversely correlated with protease levels early and TGF-beta expression late after reperfusion. SLPI plays a crucial role in early myocardial performance and postischemic inflammation after cardiac transplantation. A dual inhibitory effect on protease and TGF-beta expression might be the underlying mechanism.

COX inhibitors downregulate PDE4D expression in a clinical model of inflammatory pain.

Tumor necrosis factor-alpha (TNF-alpha) has a central role in inflammation and is modulated by prostaglandin E(2) (PGE(2)) and cyclic adenosine monophosphate (cAMP). Using microarray, quantitative real-time polymerase chain reaction (qRT-PCR), and protein detection techniques, we showed that ketorolac and rofecoxib had no significant effect on TNF-alpha gene expression in oral mucosal biopsies 3 h after surgery. They both, however, downregulated the gene and protein expression of phosphodiesterase type 4 (PDE4D), which might represent a novel mechanism contributing to their analgesic and anti-inflammatory effects.

Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor alpha and systemic immune activation.

OBJECTIVE: To provide insight into the clinical failure of the tumour necrosis factor alpha (TNFalpha) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. METHODS: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. RESULTS: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFalpha were significantly increased after treatment. CONCLUSION: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFalpha and other indicators of immune activation in this patient population. These data suggest that TNFalpha may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.

Differential mucosal susceptibility in HIV-1 transmission and infection.

HIV infection occurs primarily through mucosal surfaces, indicating that protection at mucosal sites may be crucial in prevention and treatment. The host innate and adaptive immune elements provide a level of protection, which differs between mucosal compartments, and appears to be most successful in the oral environment, where transmission is rare. In addition to the distinct oral mucosal architecture and cellular constituents, oral fluids, unlike other mucosal secretions, are rarely a vehicle for HIV infection. Multiple soluble factors may contribute to this antiviral activity, including neutralizing antibodies, secretory leukocyte protease inhibitor (SLPI), antiviral peptides such as defensins and cystatins, glycoproteins including thrombospondin and lactoferrin, and complement components. Understanding the antiviral activities of these and other potential resistance factors is becoming increasingly important in attempts to design treatments in the era of HAART resistance. In this regard, the mechanism of anti-HIV action of SLPI has recently been further elucidated by the discovery of its binding protein/receptor, which plays a key role in the infection of macrophages and may consequently be a novel therapeutic target. Continued elucidation of the unique features of mucosal HIV immunology is essential for understanding HIV pathogenesis and for developing effective vaccines and therapeutics.

(C3) The oral epithelial cell and first encounters with HIV-1.

The oral epithelium is the site of first exposure of HIV-1 to host tissues during oral sex with an infected partner or through breast-feeding by an infected mother. Although the oral epithelium is distinguishable by its apparent resistance, the mucosal surfaces represent a primary target of HIV-1. After oral exposure and swallowing, infection is detected prominently in the gastrointestinal tract, which becomes depleted of CD4+ T-cells. The oral cavity and palatine tonsils appear to resist infection and transfer to susceptible lymphoid cells in the lamina propria by local anti-HIV-1 mechanisms. In some cases, expression of these antiviral mechanisms increases after exposure to HIV-1. During primary exposure and before seroconversion, based on limited in vitro and primate data, a window of opportunity for capture of HIV-1 by the oral epithelium may exist. After seroconversion, the risk of infectious HIV-1 appearing in saliva is negligible. This report considers evidence that oral epithelium has the potential both to enable and to resist infection by HIV-1.

Immunological consequences of thalidomide treatment in Sjögren's syndrome.

OBJECTIVE: To study the immunological consequences of systemic thalidomide treatment in patients with Sjögren's syndrome. METHODS: Cytokine (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 6) and soluble receptor (sIL2R) levels were measured in patient and control plasma (n = 7), before and after thalidomide treatment. Peripheral blood mononuclear cells were examined by FACS analysis for potential changes in specific cell populations (T cells, B cells, monocytes), and for the expression of activation markers (CD25, HLA-DR), costimulatory molecules (CD40, CD40L), TNF receptors, chemokine receptors, and adhesion molecules (L-selectin (L-sel)). RESULTS: Owing to adverse effects of thalidomide, the treatment interval was limited. None the less, statistically significant changes in markers of cell activation were recorded in the four treated patients. Before treatment, HLA-DR, TNFRI, CXCRI, and CXCRII were raised in the patients compared with healthy controls (p<0.05) and their expression was down regulated after treatment. B cell numbers and expression of the adhesion molecule L-sel also declined with thalidomide. CONCLUSION: Significant changes in measures of cell activation were detected during thalidomide treatment within this limited study, which upon further investigation may offer insight into the underlying immunoregulatory pathways of thalidomide.

Nitric oxide in experimental joint inflammation. Benefit or detriment?

The host response to infection or injury initiates a cascade of events involving recruitment of leukocytes and the release of multiple inflammatory mediators. One of these mediators, nitric oxide (NO), not only represents an important microbicidal agent in host defense, but also functions as a biological signaling and effector molecule in inflammation and immunity. However, overproduction of NO can be autotoxic and contribute to tissue damage and has been implicated in pathogenesis of tumors, and infectious, autoimmune and chronic degenerative diseases. NO is generated via constitutive and inducible nitric oxide synthases (iNOS) which catalyze the oxidation of a guanidino nitrogen associated with L-arginine. Whereas endothelial NOS (eNOS) and neuronal NOS (nNOS) are constitutively expressed, iNOS is transcriptionally induced by bacterial constituents and inflammatory mediators, including TNF alpha and IL-1. In an experimental model of bacterial component-induced joint inflammation and tissue degradation, functionally distinct roles of the constitutive NOS and iNOS were demonstrated. Following systemic delivery of an arthritogenic dose of streptococcal cell walls (SCW), these bacterial peptidoglycan-polysaccharide complexes disseminate and target the peripheral joints, liver and spleen of the treated animals. Following deposition of the SCW in the peripheral joints, an initial innate inflammatory response to the bacterial components progresses into an adaptive immune response with the recruitment and activation of mononuclear phagocytes and T lymphocytes. With the release of cytokines and inflammatory mediators, there is an upregulation of gene expression for iNOS, but not the constitutive nNOS or eNOS. Nonetheless, the constitutive NOS isoforms, regulated by calcium fluxes and interaction with calmodulin, may also enhance NO production. Increased release of NO was detected not only in the synovium, but also in the circulation, and plasma levels of nitrate plus nitrite, the stable products of NO reactions, correlated with disease progression. Following inhibition of NO production with nonspecific NOS inhibitors, such as N(G)-monomethyl-L-arginine, which target all three isoforms, there is a striking therapeutic benefit with reduced signs and symptoms of erosive arthritis. In contrast, selective targeting of iNOS with N-iminoethyl-L-lysine resulted in exacerbation of the synovial inflammation and degradation of joint structures. Based on these data, it appears that the constitutive isoforms of NOS contribute to the pathophysiology of the arthropathy, and that induced NOS and NO may function, in part, in a protective pathway. Moreover, the suppression of NO following treatment with TNF alpha antagonists results in reduced inflammation and the associated synovial pathology. Collectively, these data implicate discrete roles for the NOS isoforms in the emergence of local tissue pathology and underscore the need to define the specific pathways that are being targeted for interventional strategies.

Effects of transforming growth factor-beta deficiency on bone development: a Fourier transform-infrared imaging analysis.

Transforming growth factor-beta 1 (TGF-beta1) is a cytokine member of the TGF-beta superfamily involved in the control of proliferation and differentiation of various cell types. TGF-beta1 plays an important role in bone formation and resorption. To determine the effect of TGF-beta1 deficiency on bone mineral and matrix, tibias from mice in which TGF-beta1 expression had been ablated (TGF-beta1 null) were analyzed and compared with background- and age-matched wild-type (WT) control animals by Fourier transform-infrared imaging (FTIRI) and histochemistry. FTIRI allows the characterization of nondemineralized thin tissue sections at the ultrastructural level with a spatial resolution of approximately 7 microm. The spectroscopic parameters calculated were: mineral-to-matrix ratio (previously shown to correspond to ash weight); mineral crystallinity (related to the crystallographically determined crystallite size and perfection in the apatite c-axis direction); and collagen maturity (related to the ratio of pyridinoline:deH-DHLNL collagen cross-links). Several fields were selected to represent different stages of bone development within the same specimen from the secondary ossification center to the distal diaphysis. Anatomically equivalent areas were compared as a function of age and genotype. The spectroscopic results were expressed both as color-coded images and as pixel population distributions for each of the three parameters monitored. Based on comparisons of histochemistry and FTIRI, there were distinctive age and genotype variations. At all ages examined, in the TGF-beta1 null mice growth plates, alkaline phosphatase (ALP) activity and collagen maturity were reduced, but no effect on mineral content or crystallinity was noted. In the TGF-beta1 null mice metaphyses, there was a persistence of trabeculae, but no significant alterations in mineral content or crystallinity. In contrast, mineral content, mineral crystallinity, and collagen maturity were reduced in the secondary ossification center and cortical bone of the TGF-beta1 null mice. These results, consistent with a mechanism of impaired bone maturation in the TGF-beta1 null mice, may be directly related to TGF-beta1 deficiency and indirectly to increased expression of inflammatory cytokines in the TGFbeta1 null mice.

Requirement for transforming growth factor beta1 in controlling T cell apoptosis.

Transforming growth factor (TGF)-beta1, a potent immunoregulatory molecule, was found to control the life and death decisions of T lymphocytes. Both thymic and peripheral T cell apoptosis was increased in mice lacking TGF-beta1 (TGF-beta1(-/-)) compared with wild-type littermates. Engagement of the T cell receptor enhanced this aberrant T cell apoptosis, as did signaling through either the death receptor Fas or the tumor necrosis factor alpha receptor in peripheral T cells. Strikingly, TGF-beta was localized within the mitochondria of normal T cells, and the absence of TGF-beta1 resulted in disruption of mitochondrial membrane potential (Deltapsi(m)), which marks the point of no return in a cell condemned to die. This TGF-beta-dependent regulation of viability appears dissociable from the TGF-beta1 membrane receptor-Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl-XL. Thus, TGF-beta1 may protect T cells at multiple sites in the death pathway, particularly by maintaining the essential integrity of mitochondria. These findings may have broad implications not only for T cell selection and death in immune responses and in the generation of tolerance, but also for defining the mechanisms of programmed cell death in general.

TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu.

T cell apoptosis is critical to development and homeostasis of the immune system. The most salient feature of apoptosis is the lack of an attendant inflammatory response or tissue damage. Here, we present evidence that apoptotic T cells release TGF-beta, thereby contributing to an immunosuppressive milieu. Apoptotic T cells released not only latent but also bio-active TGF-beta. Nonetheless, TGF-beta transcription was not upregulated, suggesting release of existing rather than synthesis of new TGF-beta. Localized within the intracellular membrane-bound compartment, which includes mitochondria, TGF-beta was redistributed into the cytosol following loss of mitochondrial membrane potential. TGF-beta secreted from apoptotic T cells inhibited proinflammatory cytokine production by activated macrophages to foster immune suppression. These findings broaden the potential mechanisms whereby induction of immune tolerance or deficiency occurs through T cell deletion.

Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease.

NO is an essential cytotoxic agent in host defense, yet can be autotoxic if overproduced, as evidenced in inflammatory lesions and tissue destruction in experimental arthritis models. Treatment of streptococcal cell wal1-induced arthritis in rats with N:(G)-monomethyl-L-arginine (L-NMMA), a competitive nonspecific inhibitor of both constitutive and inducible isoforms of NO synthase (NOS), prevents intraarticular accumulation of leukocytes, joint swelling, and bone erosion. Because increased inducible NOS (iNOS) expression and NO generation are associated with pathogenesis of chronic inflammation, we investigated whether a selective inhibitor of iNOS, N:-iminoethyl-L-lysine (L-NIL), would have more directed anti-arthritic properties. Whereas both L-NMMA and L-NIL inhibited nitrite production by streptococcal cell wall-stimulated rat mononuclear cells in vitro and systemic treatment of arthritic rats with L-NMMA ablated synovitis, surprisingly L-NIL did not mediate resolution of inflammatory joint lesions. On the contrary, daily administration of L-NIL failed to reduce the acute response and exacerbated the chronic inflammatory response, as reflected by profound tissue destruction and loss of bone and cartilage. Although the number of iNOS-positive cells within the synovium decreased after treatment with L-NIL, immunohistochemical analyses revealed a distinct pattern of endothelial and neuronal NOS expression in the arthritic synovium that was unaffected by the isoform-specific L-NIL treatment. These studies uncover a contribution of the constitutive isoforms of NOS to the evolution of acute and chronic inflammation pathology which may be important in the design of therapeutic agents.

Measurement of TGF-beta in biological fluids.

Transforming growth factor (TGF-beta) is an immunoregulatory cytokine produced by many different cell types, including lymphocytes and monocytes-macrophages. Two assays are described for the quantitation of TGF-beta activity in supernatant fluids. The bioassay for TGF-beta is based on the potent ability of TGF-beta to suppress lymphocyte proliferation. The radioreceptor assay is based on the ability of TGF-beta-containing supernatant fluids to inhibit the binding of radiolabeled TGF-beta to its cellular receptor. Two support protocols describe acid-activation and neutralization of TGF-beta.

Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.

Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with anti-microbial properties found in mucosal fluids. It is expressed during cutaneous wound healing. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process. We have generated mice null for the gene encoding SLPI (Slpi), which show impaired cutaneous wound healing with increased inflammation and elastase activity. The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice. We propose that SLPI is a pivotal endogenous factor necessary for optimal wound healing.

Suppression of streptococcal cell wall-induced arthritis by human chorionic gonadotropin.

OBJECTIVE: To determine whether human chorionic gonadotropin (HCG) contributes to pregnancy-associated immunosuppression, as observed clinically by an amelioration of symptoms in human autoimmune diseases, including rheumatoid arthritis, during pregnancy. METHODS: Administration of HCG was initiated 2 days prior to an arthritogenic dose of streptococcal cell wall (SCW) in nonpregnant female rats, and the development and severity of SCW-induced arthritis was monitored. Inflammatory mediators, including plasma nitrite/nitrate and cytokine levels, were measured. Inducible nitric oxide synthase (iNOS) protein and cytokine messenger RNA expression in joint tissue were compared between treated and untreated arthritic animals. RESULTS: Systemic administration of HCG resulted in a dose-dependent reduction in the clinical arthritis index. Consistent with the amelioration of clinical symptoms, HCG significantly reduced the inflammatory cell infiltration, pannus formation, and bone and cartilage degradation. Mechanistically, HCG therapy was associated with suppression of the overzealous production of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-1beta, which contribute to synovial pathology in animals with SCW-induced arthritis. Circulating nitric oxide and the amount of iNOS protein were also reduced. Furthermore, circulating transforming growth factor beta levels were elevated by the HCG, all of which suggest monocytes/macrophages as a potential target. CONCLUSION: These findings indicate that HCG exerts a protective effect in this experimental arthritis model, through modulation of inflammatory mediators.

Permissive factors for HIV-1 infection of macrophages.

Immunodeficiency, the consequence of HIV-1 infection, predisposes the host to opportunistic infections. In turn, opportunistic pathogens influence target cell susceptibility to HIV-1 infection and replication. Although the advent of highly active antiretroviral therapy (HAART) has altered these sequelae, co-infections may prevail in some parts of the world and in failed HAART regimens. Moreover, immune activation as occurs in tonsil and non-infectious mucosal inflammatory lesions may also be associated with proximal sites of viral replication. These connections between enhancement of HIV-1 infection and activation/inflammation warrant further elucidation of the factors promoting permissiveness to HIV-1 infection. Using the opportunistic pathogen Mycobacterium avium as an in vitro model, we demonstrated that co-infection facilitated HIV-1 infection of monocyte-macrophages by multiple pathways. M. avium activated NF-kappaB, the downstream consequences of which included augmented expression of tumor necrosis factor alpha and CCR5 receptors, both permissive for sustaining HIV-1 infection. Pronounced viral replication in lymph nodes co-infected with M. avium and HIV-1 paralleled these in vitro findings. Furthermore, reduction in viral burden is associated with treatment of infected or inflamed tissues, underscoring the link between immune activation and viral replication.

Impact of HIV-1 infection on VH3 gene repertoire of naive human B cells.

B cells of the largest Ig variable heavy chain gene (VH) family, VH3, are reportedly decreased in patients with late stage HIV-1 disease. This deficit may contribute to their impaired responses to infections and vaccines. We confirmed that the VH3 family was underrepresented in serum IgM proteins, with a 45% decrease in patients with advanced HIV-1 disease. However, the proportion of VH3 within VH(1-6) IgM mRNA from peripheral B cells did not differ from that of control subjects (mean +/- SD, 57.1 +/- 9.7 vs 61.1 +/- 8. 7%). Similarly, within VH(1-6) IgD mRNA, which even more closely represents the unstimulated naive repertoire, the relative expression of VH3 mRNA was comparable in the two groups. Moreover, the frequency of individual genes within the VH3 family for IgD, particularly genes which encode putative HIV-1 gp120 binding sites, also was normal in HIV-1-infected patients. However, VH3 family expression for IgG mRNA was significantly decreased (17%) and VH4 IgG was increased (33%) relative to other VH families in advanced HIV-1-infected patients. Thus, the changes in VH family expression were more readily apparent in previously activated IgG "memory" B cell populations and, likely, in cells actively producing IgM rather than in resting naive cells. The presence of a relatively normal naive VH3 IgM and IgD mRNA repertoire in resting cells supports the prospect that with proper stimulation, particularly in conjunction with effective antiviral therapy, vigorous humoral immune responses to infections and vaccines may be elicited in this high-risk population.