Capiluppi B

Neurological Symptoms during Primary Human Immunodeficiency Virus (HIV) Infection Correlate with High Levels of HIV RNA in Cerebrospinal Fluid

This analysis involves 22 patients with diagnosed symptomatic human immunodeficiency virus (HIV) infection. Neurologic symptoms were present in 11 patients, ranging from severe and persistent headache to clinical signs suggestive of meningitis. A strong correlation between neurological symptoms and cerebrospinal fluid (CSF) viral load was found. The mean CSF HIV ribonucleic acid (RNA) level was 4. 12 log for patients with neurological symptoms and 2.58 log for patients without neurological symptoms (P<.00001). Plasma viral load alone does not correlate or predict central nervous system (CNS) involvement. In our sample of patients, HIV RNA levels could be detected in most patients regardless of the presence of neurological symptoms. Moreover, early treatment including drugs with high levels of penetration in the CNS must be considered for patients with primary HIV infection.

Escape of monocyte-derived dendritic cells of HIV-1 infected individuals from natural killer cell-mediated lysis

Objective: To verify whether the in vitro sensitivity of immature dendritic cells (iDC) to lysis by autologous natural killer (NK) cells from HIV-infected individuals might be correlated with HIV disease progression. Design: Both dendritic cells (DC) and interlekin (IL)-2 activated NK cells were obtained from 13 HIV-infected individuals early after seroconversion and not receiving highly active antiretroviral therapy (HAART) and from 14 individuals with chronic HIV infection under HAART. The rate of NK cell-mediated killing of autologous iDC was correlated with classical parameters of HIV evolution. Methods: Peripheral blood monocytes obtained from the Ficoll-derived leukocyte fraction after adherence to plastic were stimulated with granulocyte–macrophage colony stimulating factor plus IL-4 to induce their differentiation into iDC to be used as target cells in a standard 4-h cytotoxicity assay. A fraction of autologous leukocytes was stimulated with IL-2 to induce activation of NK cells to be used as effector cells. Results: During early HIV infection the extent of ex vivo lysis of monocyte-derived DC by activated autologous NK cells was inversely and directly correlated with the levels of viraemia and with the percentage of circulating CD4 T cells, respectively. In contrast, the capacity of NK cells to kill iDC was lost independently of the levels of plasma viraemia or the concurrence of HAART in chronically infected individuals. Addition of exogenous HIV Tat during the cytotoxicity assay inhibited NK cell-mediated lysis of DC. Conclusions: NK cell-mediated immune surveillance against infected DC may be effective only during early HIV infection and may not be restored by HAART.

Viral load and burden modification following early antiretroviral therapy of primary HIV-1 infection.

OBJECTIVE The aim of this study was to monitor the effect on viral DNA and RNA of early treatment with highly aggressive antiretroviral therapy (HAART), in comparison with zidovudine (ZDV) monotherapy or no treatment in subjects with primary HIV-1 infection (PHI). DESIGN AND METHODS Of the 28 patients selected, four were untreated, four received ZDV alone, 10 received a triple combination (ZDV, lamivudine (3TC) and saquinavir (SQV)) and 10 received a quadruple combination (ZDV, 3TC, SQV and ritonavir (RTV)). Seroconversion was monitored by means of Western blot profile analysis. A quantitative polymerase chain reaction (PCR) assay in the HIV gag region was used to monitor viral DNA and the nucleic acid sequence based amplification (NASBA) system for viraemia (HIV-RNA). RESULTS There was a certain level of heterogeneity in the baseline values of HIV-DNA and RNA. Early HAART led to a rapid recovery in the number of CD4 cells and the CD4/CD8 cell ratio and a reduction in HIV-RNA to undetectable levels, which was significantly greater than in the untreated patients or those treated with ZDV. Although a reduction in DNA levels was also observed in the HAART-treated subjects, this variation was not significant. CONCLUSIONS The parameters of viral replication and CD4 cell recovery were only slightly better in the patients receiving ZDV monotherapy than in the untreated patients, thus confirming that the course of the infection is hardly affected by the monotherapy. The early introduction of HAART greatly reduces plasma viraemia and restores the number of CD4 cells for up to 1 year. HIV-DNA remains detectable, although at low levels, thus confirming that the early established reservoir of infected cells is little affected. Longer periods of observation and the introduction of complementary approaches, such as immunomodulatory therapies, will provide further information concerning the possibility of radically interfering with the natural evolution of the disease.

Anti-Cell Antibodies in Exposed Seronegative Individuals with HIV Type 1-Neutralizing Activity

Despite repeated exposures to HIV-1, some individuals remain seronegative. This study reports that sera from a fraction of exposed seronegative (ESN) subjects showed HIV-neutralizing activity; 5 of 17 ESN sera and none of 17 controls neutralized two different HIV-1 primary isolates (range of neutralizing titers: 1/20 to 1/60). The neutralizing activity was associated with the IgG fraction of 4 of 4 neutralizing ESN sera. Moreover, in 11 of 17 and 9 of 17 ESN sera (but none of the control sera) we found antibodies against HLA class I and CD4, respectively. One of the ESN sera (EU22) neutralized efficiently the primary virus derived from the seropositive partner and showed a good broadly cross-reactive neutralization. Immunoadsorption of two IgG fractions from EU19 and EU22 on peripheral blood mononuclear cells (PBMC) removed virus-neutralizing antibodies. The correlations between the ESN status and neutralizing activity (p<0.05), anti-HLA antibodies (p<0.0002), and anti-CD4 antibodies (p<0.001) were statistically significant. However, there was no statistically significant correlation between neutralizing activity and either anti-HLA or anti-CD4 antibodies. It can therefore be said that exposure to HIV-1 without seroconversion is, in some individuals, associated with HIV-neutralizing antibodies (not directed against viral antigens) and/or with anti-cell autoantibodies, which are possibly specific for cellular antigens involved in the infection/entry process.