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Three major characteristics of human immunodeficiency virus (HIV) infection define HIV as neurotropic. 1) Clinically, distinct neurological syndromes are associated with HIV infection and 2) presence of the virus as well as 3) pathological changes can be demonstrated in the central nervous system. Spread of HIV to the brain seems to be the general rule. Virus expression appears to be restricted during the asymptomatic period but increases with severity of HIV infection. Whether this reflects the emergence of virus variants with increased replicative capacity in brain cells has yet to be elucidated.

Two partially overlapping 19 and 22 amino acids long peptides representing a highly immunogenic site of the transmembranous glycoprotein (gp41) of human immunodeficiency virus (HIV) were used as antigen in ELISA tests. The results of antibody determination with this assay were compared with those of three or more conventional ELISAs and Western blot (WB) tests and radioimmunoprecipitation assay. Twenty-six sera from patients with AIDS or LAS and from asymptomatic carriers of HIV infection all showed a pronounced reaction in the peptide ELISA as well as positive results with other tests. In contrast, 27 sera from laboratory workers and blood donors were negative by all tests. A group of 39 blood donor sera, which had shown false positive or ambiguous results in the ELISAs and sometimes in WB tests employed for confirmation, also were negative in all cases with the peptide ELISA. Consecutive samples collected from individuals with primary HIV infection were also analyzed. In 6 out of 9 cases, the peptide ELISA revealed an antibody response within one month after onset of clinical symptoms and sensitivity for antibody detection equaled that of other ELISA tests. Eight sera from five West African persons infected with HIV-related viruses did not react in the peptide ELISA, reflecting differences in properties of the envelope components. The peptide ELISA used in this study appears to represent a simple technique employing chemically synthesized antigen for accurate and sensitive estimation of antibodies to the HIV group of nontransforming human retroviruses.

A new human retrovirus of West African origin (SBL-6669) has been isolated from a patient with immunological and clinical signs of immunodeficiency. Using radioimmunoprecipitation assays (RIPA) and Western blot (WB) tests with human sera, the new virus isolate has been compared with HTLV-IV, LAV-II, and the HTLV-IIIB prototype strain of the human immunodeficiency virus (HIV). The West African isolates appeared to be members of the same virus group since their glycoproteins were antigenically indistinguishable. West African sera showed no detectable cross reaction with HTLV-IIIB glycoproteins. The external glycoprotein in the different virus strains only showed minor variations in size. The size of the transmembranous protein was not unambiguously defined. In the West African virus isolates a 30-35 kD protein was seen similar to the protein previously described possibly to represent this component. However, in SBL-6669 a distinct 41 kD protein was also identified. There were interstrain variations in the size of several viral proteins among the West African virus isolates. Only minor differences were seen between SBL-6669 and LAV-II. The variations were most pronounced in two core proteins corresponding to the 19 kD and 24 kD proteins of HTLV-IIIB. In addition, West African human retroviruses appear to differ in pathogenicity. LAV-II and SBL-6669 are associated with immunodeficiency, whereas HTLV-IV was isolated from healthy individuals. Since further spread of these viruses to other parts of the world is imminent, it is necessary to consider their antigenic and immunogenic properties in serodiagnosis of HIV infections and in planning for immunoprophylactic interventions.

The antibody response in 20 homosexual men with symptomatic primary HIV infection was studied with ten different antibody assays (enzyme-linked immunosorbent assays, indirect immunofluorescence assays, radioimmunoprecipitation [RIPA], and western blot). HIV antibodies were detectable by all the assays within 2 months after onset of illness. RIPA and western blot were more sensitive than the other assays--all serum samples obtained at 2 weeks and after were reactive. In all cases, the first serum sample reactive by RIPA precipitated gp160 whereas, by western blot, antibodies to p24 were first recognised. This study shows the necessity of including gp160 and p24 in any assay to detect early antibody response in primary HIV infection. 5 patients were studied by virus isolation. During the 2 first weeks after onset of symptoms, HIV was demonstrated in cell-free plasma in all cases and, in 4 cases, also in peripheral blood mononuclear cells. Samples obtained later contained demonstrable infectious virus in only 1 of 4 cases. Thus a phase of viraemia precedes the antibody response in symptomatic primary HIV infection.

A malignant glioma cell line was infected with the human T-lymphotropic virus type IIIB isolate of the human immunodeficiency virus. Infection appeared to be latent rather than productive. Through contact with monocytic or lymphoid cells, the virus present in the glioma cells could be transmitted and gave rise to a fully productive infection.

Isolation of the human immunodeficiency virus (HIV) has been attempted from the cerebrospinal fluid (CSF) of 29 subjects with varying severity of HIV infection. Virus could be isolated from patients in all stages of disease including patients with primary HIV infection and asymptomatic carriers. In the early stages of infection free virus was infrequently present in the CSF but could be isolated from the cells present in CSF. This suggests that HIV may reach the brain at a very early stage of infection and that initially there is little production of virus from infected cells. In the late stages of HIV infection, associated with increasing severity of immunodeficiency, free virus could readily be isolated from the CSF. With one exception, all of these patients had neurological and/or psychiatric symptoms, as compared to only 2 (of 13) subjects in the early stages of infection. All patients with HIV-specific antibodies in serum had antibodies also in CSF. Examined by a radioimmunoprecipitation assay, CSF was more often found to contain antibodies to the precursor (p55) of viral core proteins than the corresponding serum of the patients. We propose that immune disturbances have an essential pathogenic role in the neurological/psychiatric symptoms associated with HIV infection, possibly through allowing increased viral expression in the central nervous system.

Human immunodeficiency virus (HIV) has been isolated from plasma in 6 of 7 patients showing clinical symptoms of a primary HIV infection. Parallel cultures from peripheral blood mononuclear cells (PBMC) yielded virus in 5 patients. In one case, virus could only be isolated from the cerebrospinal fluid but not from peripheral blood. Detectable viremia was transient and preceded the appearance of HIV specific antibodies. After cessation of acute symptoms, the frequency of HIV isolations was similar to that of asymptomatic carriers (23 and 26%, respectively). The role of the immune response in terminating detectable viremia remains to be established.

A model system was established for studies of humoral and cellular immunity to human immunodeficiency virus (HIV) antigens after vaccination. Macaques (Macaca fascicularis) were immunized with purified HIV, an infected cell extract rich in gp120 or polypeptides of cloned genes representing parts of p24, gp41, and gp120. Western blot analysis best showed the appearance of antibodies to nucleocapsid proteins, and antibodies to higher molecular weight envelope glycoproteins were better demonstrated by radioimmunoprecipitation. With whole HIV, antibodies to p24 appeared first, and sometimes were the only ones to be demonstrable. Several immunizations with HIV or recombinant polypeptides were required to obtain antibodies to gp120, and the responses were weak. Although the envelope-specific response was weak, this was the only component that mediated neutralizing capacity. Escherichia coli-derived viral transmembrane polypeptide (g)p41 also had a poor immunizing effect. IgG synthesis from B cells in vitro was demonstrable to antigens and generally paralleled the antibody titers of sera after multiple immunizations. The HIV-specific lymphocyte proliferation response as measured by DNA synthesis was best seen with polypeptide p24-15, followed by the other antigens.

Sera from individuals infected with human immunodeficiency virus (HIV) and HIV-related West African viruses can mediate high-titered, virus-specific antibody-dependent cellular cytotoxicity (ADCC) in all stages of infection. No cross-reactive ADCC can be detected between HIV and HIV-related West African strains LAV-2, HTLV-IV, and SBL-6669. Because these two groups of viruses have antigenically distinct envelope glycoproteins, ADCC-mediating antibodies are most likely directed against envelope antigens. For HIV-specific ADCC, this was further confirmed by using sera reacting with HIV envelope but negative for antibodies against viral core antigens.

Human immunodeficiency virus (HIV) strains can be separated into two types: HIV and HIV-related West African viruses. Site-directed serology using synthetic peptides offers possibilities for the determination of type-specific antibodies. A 22-amino-acid peptide with the sequence Ala-Ile-Glu-Lys-Tyr-Leu-Glu-Asp-Gln-Ala-Gln-Leu-Asn-Ala-Trp-Cys-Ala-Phe-Arg-Gln - Val-Cys representing a conserved region of the transmembranous protein of simian T-cell lymphotropic virus-type III (STLV-III; related to West African HIV) was used as antigen in an enzyme-linked immunosorbent assay (ELISA). In parallel, tests were performed with a pair of previously described peptides, including the homologous region of the glycoprotein (gp) 41 of the HIV strain HTLV-IIIB. In tests with three groups of 20 sera it was shown that the different peptide ELISAs allowed a categorical distinction of antibodies to the two types of HIV. Tests using peptide antigens may provide excellent opportunities for large-scale testing for type-specific antibodies against HIV. The tests are simple, sensitive and specific and are readily standardized.

We present an improved culture technique for propagation of human immunodeficiency virus (HIV) strains that grow slowly, yield low reverse transcriptase activity and can be transmitted poorly, if at all, to cell lines. By using the Jurkat-tatIII cell line 29 (of 30) of these slow/low HIV strains, including one West African strain, could be shown to replicate over a period of several weeks.

Isolation of the human immunodeficiency virus (HIV) has been attempted from the cerebrospinal fluid (CSF) of 63 subjects at different stages of HIV infection, including asymptomatic carriers and patients with or without neurologic or psychiatric complications. In addition blood was collected from 40 of these subjects for virus isolation. HIV could be isolated from the CSF at all clinical stages with an overall frequency of 40%. In contrast, the frequency of HIV isolation from the blood was lower (32%) at the early stages of infection than in patients with severe disease (77%). HIV isolation from the CSF was more frequently positive in patients with neurologic or psychiatric complications than in patients showing no such disturbances (48 and 32%, respectively).

The sensitivity and specificity of radioimmunoprecipitation assay (RIPA) and Western blot (WB) test were compared by use of a collection of 183 sera, representing different categories of individuals, noninfected or infected with the human immunodeficiency virus (HIV). The sera were subdivided on the basis of their reactivity in at least two anti-HIV enzyme-linked immunosorbent assays (ELISA); 53 sera were negative and 61 sera were positive in both tests, whereas 69 sera showed ambiguous reactions. The reaction patterns in RIPA could be divided into 6 different groups. The same grouping could to some extent be applied to the results of WB test. RIPA provided the most efficient means for identification of the large viral envelope glycoproteins, gp120/160, whereas gp41 was detected more effectively by WB. Internal virus components reacted to a varying extent with specific antibodies in the two tests. The reaction with pol products was more pronounced with the WB tests in which extracellular material was used as antigen. In a few WB tests, however, the reaction with internal components did not reflect a prior HIV infection. No such ambiguity was observed with RIPA, reflecting the advantage of a test that uses a minimally denaturated antigen and provides appropriate conditions for identification of the large viral glycoproteins. The practical choice of confirmatory tests to be used in diagnostic laboratories requires evaluation of both the sensitivity and specificity of the tests but also their economy and convenience.

According to their capacity to replicate in vitro, human immunodeficiency virus (HIV) isolates can be divided into two major groups, rapid/high and slow/low. Rapid/high viruses can easily be transmitted to a variety of cell lines of T-lymphoid (CEM, H9, and Jurkat) and monocytoid (U937) origin. In contrast, slow/low viruses replicate transiently, if at all, in these cell lines. Except for a few isolates, the great majority of slow/low viruses replicate in peripheral blood mononuclear cells and Jurkat-tatIII cells constitutively expressing the tatIII gene of HIV-1. The viruses able to replicate efficiently cause syncytium formation and are regularly isolated from immunodeficient patients. Poorly replicating HIV isolates, often obtained from individuals with no or mild disease, show syncytium formation and single-cell killing simultaneously or, with some isolates, cell killing only.

Despite the great advances made in controlling human immunodeficiency virus type 1 ( HIV-1) infection with antiretroviral drug treatment, a safe and efficacious HIV vaccine has yet to be developed. Here, we discuss why clinical trials and vaccine development for HIV have so far been disappointing, with an emphasis on the lack of protective antibodies. We review approaches for developing appropriate HIV immunogens and the stimulation of long-lasting B-cell responses with antibody maturation. We conclude that candidate reagents in the pipeline for HIV vaccine development are unlikely to be particularly effective. Although the major funders of HIV vaccine research and development are placing increasing emphasis on clinical product development, a genuine breakthrough in preventing HIV infection through vaccines is more likely to come from novel immunogen research. [ABSTRACT FROM AUTHOR]

. Dang LVP, Nilsson A, Ingelman-Sundberg H, Cagigi A, Gelinck LBS, Titanji K, De Milito A, Grutzmeier S, Hedlund J, Kroon FP, Chiodi F (Karolinska Institutet, Stockholm; Karolinska University Hospital Huddinge, Stockholm; Erasmus Medical Center, Rotterdam, The Netherlands; Emory University School of Medicine, Atlanta, GA, USA; Karolinska Institutet, Stockholm; The Soder Hospital, Stockholm; Karolinska University Hospital, Solna, Sweden; Leiden University Medical Center (LUMC), Leiden, The Netherlands). Soluble CD27 induces IgG production through activation of antigen-primed B cells. J Intern Med 2012; 271: 282-293. Objectives. High levels of soluble CD27 (sCD27), a marker of immune activation, are found in several infectious [including human immunodeficiency virus type-I (HIV-1)] and autoimmune diseases; however, a direct biological effect of sCD27 on B cells has not been established. The aim of this study was to investigate whether sCD27, by binding to CD70, can induce immunoglobulin G (IgG) production from B cells. Methods. B cells from healthy and HIV-1-infected individuals were cultured with recombinant human sCD27 (rhsCD27), and IgG production was measured. The role of rhsCD27 in inducing the expression of transcription factors involved in plasma cell differentiation was evaluated. Furthermore, we investigated the impact of different cytokines on the modulation of CD70 expression on B cells and the relationship between levels of IgG and sCD27 in serum from healthy and HIV-1-infected individuals. Results. We demonstrated that rhsCD27 induced IgG production from antigen-primed (CD27+) B cells. This effect was mediated by rhsCD27 binding to CD70 on B cells leading to activation of Blimp-1 and XBP-1, transcription factors associated with plasma cell differentiation. We found a significant correlation between levels of serum sCD27 and IgG in HIV-1-infected individuals and healthy controls. Conclusions. sCD27 may act to enhance immunoglobulin production and differentiation of activated memory or recently antigen-experienced B cells, thus providing an activation signal to antigen-experienced B cells. This mechanism may operate during autoimmune and chronic infectious diseases, situations in which continuous immune activation leads to upregulation of CD70 expression and increased sCD27 cleavage. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses issues related to immunodeficiency syndrome (AIDS), a disease caused by human immunodeficiency virus (HIV).

Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F (Karolinska Institutet, Stockholm, Sweden; National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; San Raffaele Scientific Institute, Milan, Italy). The role of IL-1β in reduced IL-7 production by stromal and epithelial cells: a model for impaired T-cell numbers in the gut during HIV-1 infection. J Intern Med 2010; 268: 181–193. Objectives. Interleukin (IL)-7 is a key cytokine in T-cell homeostasis. Stromal cells, intestinal epithelial cells and keratinocytes are known to produce this cytokine. The mechanisms and cellular factors regulating IL-7 production are still unclear. We assessed whether IL-1β and interferon (IFN)-γ, cytokines produced during inflammatory conditions, may impact on IL-7 production. Design. We used human intestinal epithelial cells (DLD-1 cell line) and bone marrow stromal cells (HS27 cell line), known to produce IL-7; IL-7 production was evaluated at the mRNA and protein levels. To assess whether treatment of HS27 cells with IL-1β and/or IFN-γ leads to changes in the gene expression of cytokines, Toll-like receptors (TLRs) and chemokines, we analysed gene expression profiles using the whole-genome microarray Human Gene 1.0 ST. Results. We found that IFN-γ enhanced the expression of IL-7 mRNA ( P < 0.001) in both cell lines. IL-1β treatment led to a significant down-regulation ( P < 0.001) of IL-7 mRNA expression in both cell lines. The IL-7 concentration in supernatants collected from treated DLD-1 and HS27 cell cultures reflected the trend of IL-7 mRNA levels. The gene profiles revealed dramatic changes in expression of cytokines and their receptors (IL-7/IL-7Rα; IL-1α,IL-1β/IL-1R1; IFN-γ/IFN-γR1), of IFN regulatory factors (IRF-1 and 2), of TLRs and of important chemo-attractants for T cells. The microarray results were verified by additional methods. Conclusions. Our results are discussed in the setting of inflammation and T-cell survival in the gut compartment during HIV-1 infection where stromal and epithelial cells may produce factors that contribute to impaired IL-7 homeostasis and homing of T cells. [ABSTRACT FROM AUTHOR]

To define the amino acids involved in IgG subclass reactivity to two overlapping HIV-1 gp41 (E34/32; amino acid positions 582-613) peptides, sera from 18 HIV-infected individuals were studied. Peptides mimicking E34 but with single amino acid deletions or glycine substitutions were used to define the amino add residues necessary for antibody binding. Two dominating immunogenic epitopes, containing highly hydrophilic amino acids, were found on the original peptide. Further analysis was undertaken with two corresponding omission sets of dodecapeptides representing halves of the complete E34 plus a terminal cystein peptide. The subclass reactivities usually differed between the patients with regard to the epitopes with which the different IgG subclasses reacted and also to the importance of different amino acids in antibody binding. The 600 glycine and the 601 lysine were involved in the binding of all IgG1,2 and 4 and most IgG3. The development of E34/32-reactive IgM and IgG subclasses showed different patterns in four patients with primary HIV infections, contradicting the existence of a general pattern for the development of IgG subclasses to this peptide. The findings suggest that different progenitor clones are selected for synthesis of the different subclasses. [ABSTRACT FROM AUTHOR]

Low concentrations of serum obtained from a patient with acquired immunodeficiency syndrome (AIDS) enhanced the replication of human immunodeficiency virus type I (HIV-1) in a particular subclone of the CD4-positive monocytoid cell line U937 clone 2. Cells of this subclone have a high expression of Fc receptors and a considerable degree of Fc-mediated phagocytic activity. IgG purified from the serum was also able to enhance the replication. These results indicate that low concentrations of human anti-HIV antibody may enhance HIV replication on human monocyte- macrophages. Furthermore, two mouse IgG1 monoclonal antibodies against gp120, the envelope g1ycoprotein of HIV-1, also induced enhancement at low concentrations. The binding of radiolabelled gp120 to the cells was increased at the same low concentrations. Antibodies against envelope glycoproteins may cause enhancement of HIV infection. Both normal and enhanced replication of H IV were completely inhibited by the masking of the binding site of CD4 molecules with F(ab′)2 fragments of anti-CD4 antibody. Moreover, CD4-positive, FcγRI-negative K562 cells and mouse macrophages failed to show any infection in the presence of antibody. These results suggest that CD4 molecules on the cell surface are necessary to cause enhancement of infection of HIV on monocyte-macrophages. [ABSTRACT FROM AUTHOR]

The article reports on neutralizing antibodies at mucosal areas for HIV vaccine. Three topics covered at a Stockholm, Sweden conference titled "HIV neutralizing antibodies: relevance to pathogenesis and vaccines" are presented. The importance of humoral immunity and HIV-1 neutralization are covered.

Background: HIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation.Methods: We propose a mixed-methods study amongst young people aged 13-24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13-24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue.Discussion: This study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information on successful strategies for providing PrEP to young people in sub-Saharan Africa.Trial Registration: ClinicalTrials.gov NCT03986970 . Registered on 14 June 2019. [ABSTRACT FROM AUTHOR]