Fiorenza Cocchi

Identification of RANTES, MIP-1α, and MIP-1β as the Major HIV-Suppressive Factors Produced by CD8+ T Cells

Evidence suggests that CD8+ T lymphocytes are involved in the control of human immunodeficiency virus (HIV) infection in vivo, either by cytolytic mechanisms or by the release of HIV-suppressive factors (HIV-SF). The chemokines RANTES, MIP-1α, and MIP-1β were identified as the major HIV-SF produced by CD8+ T cells. Two active proteins purified from the culture supernatant of an immortalized CD8+ T cell clone revealed sequence identity with human RANTES and MIP-1α. RANTES, MIP-1α, and MIP-1β were released by both immortalized and primary CD8+ T cells. HIV-SF activity produced by these cells was completely blocked by a combination of neutralizing antibodies against RANTES, MIP-1α, and MIP-1β. Recombinant human RANTES, MIP-1α, and MIP-1β induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). These data may have relevance for the prevention and therapy of AIDS.

Role of β-Chemokines in Suppressing HIV Replication

Fiorenza Cocchi et al. (1) found that three different 1-chemokines (RANTES, MIPlot, and MIP-11) produced by CD8+ T lymphocytes suppress human immunodeficiency virus (HIV) replication in peripheral blood mononuclear cells (PBMC). Moreover, neutralizing antibodies to all three chemokines eliminate the activity against HIV detected in CD8+ cell supernatants (1). They conclude that these chemokines are responsible for the CD8+ cell anti-HIV

HIV-1-suppressive factors are secreted by CD4+ T cells during primary immune responses

CD4+ T cells are required for immunity against many viral infections, including HIV-1 where a positive correlation has been observed between strong recall responses and low HIV-1 viral loads. Some HIV-1-specific CD4+ T cells are preferentially infected with HIV-1, whereas others escape infection by unknown mechanisms. One possibility is that some CD4+ T cells are protected from infection by the secretion of soluble HIV-suppressive factors, although it is not known whether these factors are produced during primary antigen-specific responses. Here, we show that soluble suppressive factors are produced against CXCR4 and CCR5 isolates of HIV-1 during the primary immune response of human CD4+ T cells. This activity requires antigenic stimulation of naïve CD4+ T cells. One anti-CXCR4 factor is macrophage-derived chemokine (chemokine ligand 22, CCL22), and anti-CCR5 factors include macrophage inflammatory protein-1α (CCL3), macrophage inflammatory protein-1β (CCL4), and RANTES (regulated upon activation of normal T cells expressed and secreted) (CCL5). Intracellular staining confirms that CD3+CD4+ T cells are the source of the prototype HIV-1-inhibiting chemokines CCL22 and CCL4. These results show that CD4+ T cells secrete an evolving HIV-1-suppressive activity during the primary immune response and that this activity is comprised primarily of CC chemokines. The data also suggest that production of such factors should be considered in the design of vaccines against HIV-1 and as a mechanism whereby the host can control infections with this virus.

Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of β chemokines and RNases

T-cell-derived soluble factors that inhibit both X4 and R5 HIV are recognized as important in controlling HIV. Whereas three β chemokines, regulated-on-activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α, and MIP-1β, account for the suppression of R5 HIV by blockade of HIV entry, the major components responsible for the inhibition of X4 HIV strains have not been identified previously. We identify these factors primarily as a mixture of three β chemokines [macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC), and I-309] and two RNases (angiogenin and RNase 4) of lesser potency and show that in a clade B population, some correlate with clinical status and are produced by both CD4+ and CD8+ T cells (chemokines, angiogenin) or only by CD8+ T cells (RNase 4). The antiviral mechanisms of these HIV X4-suppressive factors differ from those of the previously described HIV R5-suppressive β chemokines.

Response: Role of β-Chemokines in Suppressing HIV Replication

Table 2. Effect of neutralizing antibodies to ,B-chemokines on CAF-mediated suppression of a 1-chemokine-sensitive HIV-1 isolate. As described in Table 1, a 50% dilution of two CAFcontaining culture fluids was pretreated with control antibody or with a mixture of neutralizing antibodies to RANTES, MIP-1co, and MIP-113 before addition to HIV-1sv-infected CD4+ cells. The effect of these treatments on the percentage of suppression of HIV replication by the CAF-containing medium relative to control medium-treated cells is presented. Virus replication in the control culture receiving no CAF was about 150,000 cpm of RT activity per milliliter of culture fluid. The chemokine levels in CAF fluid 1 were 689,132, and 520 pg/ml for RANTES, MIP-1(x, and MIP-1 1, respectively. For CAF fluid 2, we selected a CD8+ cell culture supernatant with high chemokine levels, which were 14,161,14,519, and 11,450 pg/ml for RANTES, MIP-1 a, and MIP-1 ,B, respectively. Fluids receiving the anti-chemokine antibodies showed complete elimination of the chemokines as measured by ELISA.

Soluble interleukin-2 receptor decrease in the sera of HIV-infected patients treated with zidovudine.

Laboratory parameters which are modified following administration of zidovudine are becoming increasingly useful in monitoring the efficacy of treatment of early stages of HIV-1 infection. The serum levels of soluble interleukin (sILR)-2 receptor, which have been reported to increase early in HIV-1 infection, were found to be significantly lower in 24 patients being treated with zidovudine than in 69 patients who were not treated, 28 of whom had CD4+ counts greater than 400 x 10(6)/l, and 41 less than 400 x 10(6)/l, respectively (P less than 0.0001). A prospective study group of 33 subjects treated with zidovudine demonstrated a decrease in sIL-2R during therapy (base values 2113 +/- 1131 versus 1444 +/- 728 after 90 days of therapy; P less than 0.0007). The reduction of sIL-2R was greater in those subjects were p24 antigen became negative during treatment. sIL-2R therefore seems to be a useful tool in the monitoring of therapy with zidovudine.