Human immunodeficiency virus (HIV) controllers are rare individuals who spontaneously control HIV type 1 replication for 10 years or more in the absence of antiretroviral treatment. In the present study, HIV controllers (n ‫؍‬ 11) maintained potent HIV-specific CD4 responses in spite of very low antigenic loads. Their CD4؉ central memory T (T CM ) cells were characterized by near-normal numbers and preserved interleukin-2 (IL-2) secretion in response to HIV antigens and uniformly high expression of the survival receptor IL-7 receptor ␣ (IL-7R␣). Controllers expressed CCR7 at higher levels than uninfected controls, suggesting differences in T CM -cell homing patterns. CD4؉ effector memory T (T EM )-cell responses were polyfunctional in HIV controllers, while IL-2 secretion was lost in viremic patients. Cytokine production was three times higher in controllers than in treated patients with undetectable viral loads, suggesting an intrinsically more efficient response in the former group. The total CD4؉ T EM -cell pool underwent immune activation in controllers, as indicated by increased HLA-DR expression, decreased IL-7R␣ expression, a bias towards gamma interferon production upon polyclonal stimulation, and increased macrophage inflammatory protein 1␤ secretion associated with chronic CCR5 down-regulation. Thus, HIV controllers showed a preserved CD4؉ T CM -cell compartment and signs of potent functional activation in the CD4؉ T EM -cell compartment. While controllers did not show the generalized immune activation pattern associated with disease progression, they had signs of immune activation restricted to the effector compartment. These findings suggest the induction of an efficient, nondetrimental type of immune activation in patients who spontaneously control HIV.

SummaryHIV infection activates abnormally the immune system and the chronic phase is accompanied by marked alterations in the CD8 compartment. The expression of CD127 (IL-7R alpha chain) by memory CD8 T lymphocytes in HIVinfected patients is analysed and reported. The memory CD8 T cell subset was characterized by expression of CD45RA and CD27 markers, and CD127 cell surface expression was measured ex vivo by four-colour flow cytometry. HIV infection was associated with a fall in the proportion of CD127

The IL-7R α-chain and the common γ-chain (γc) are both components of IL-7R. Human plasma harbors soluble forms of IL-7R (sIL-7Rα and sγc) that are detected and assayed by Western blotting, showing that the levels of sIL-7Rα are higher than the levels of sγc (47.5 ng/ml and 1.5 ng/ml, respectively). Gel electrophoresis and tandem mass spectrometry used to analyze deglycosylated, affinity-purified protein showed that sIL-7Rα is generated through differentially spliced mRNA, not by membrane receptor shedding. Plasma sIL-7Rα and sγc are present as heterocomplexes and sγc was found to be mainly associated with sIL-7Rα. The affinities of two IL-7 binding sites (Kd = 35 ± 8 pM and Kd = 3 ± 1 nM) were similar to that of the membrane receptor, suggesting that the sIL-7Rα/sγc complex retains high affinity for IL-7. sIL-7Rα mRNA is constitutively present among peripheral T lymphocytes and is down-modulated in vitro by IL-7. Chronically HIV-1-infected patients (n = 20) showed no significant (p > 0.714) variation in sγc levels and a significant (p < 0.0014) 2-fold decrease in plasma sIL-7Rα levels compared with those in control healthy individuals. Plasma IL-7 and sIL-7Rα levels did not show any obvious relationship.

So far, studies of Leishmania persistence in mice have used injections of parasites administered either intravenously in the tail vein or subcutaneously in the footpad. These routes poorly reflect the natural conditions when the sandfly delivers metacyclic promastigotes intradermally. In this study B10D2 and BALB/c mice were inoculated within the ear dermis with 10 4 Leishmania major metacyclic promastigotes. The parasite load was monitored by quantitative PCR in different tissues from the dermal inoculation site to distant tissues. The two sites of multiplication and persistence of parasites were the site of L. major inoculation and the draining lymph node (DLN), with a different pattern in the two mouse inbred lines. These two organs were the only sites harboring parasites 12 months postinoculation, with the DLN of BALB/c mice harboring around 10 7 parasites, a stable load from months 3 to 12. In these two sites, 8 and 12 months after inoculation, interleukin 4 (IL-4), gamma interferon, and inducible nitric oxide synthase transcripts parallel the parasite load while IL-10 transcript levels remain high. In addition, at early time points until month 3, parasite DNA was also detected in distant tissues such as the contralateral noninoculated ear or the tail skin, indicating that blood was at least transiently disseminating the parasites. In contrast, L. major DNA in liver, spleen, and femoral bone marrow remained sporadic in mice of both lines. This study is discussed within the framework of Leishmania transmission from the vertebrate host to the sandfly vector, a complex process still poorly understood.Leishmaniasis currently affects some 12 million individuals in 88 countries, and at least 350 million people are exposed to the risk of the Leishmania parasite inoculation (see the World Health Organization information at http://www.who.int/emc /diseases/leish/leis.html). It is well established that in Leishmania transmission areas, individuals may harbor the parasites at very low levels, without developing symptoms. These individuals, considered asymptomatic carriers, are likely to transmit the parasite to the hematophagous sandfly vector or, as shown recently, via blood transfusion (16). Moreover, Leishmania spp. may persist in cured hosts after drug therapy (for a review, see reference 1) and be reactivated after immunosuppression, for instance, in human immunodeficiency virus-infected people (3). The capacity of the parasite to establish persistent infection as a means to achieve its transmission and hence maintenance of its life cycle is a process common to many parasites (9, 10). Little is known on the mechanisms underlying persistence of Leishmania parasites in their vertebrate host and transmission to the sandflies, pool-feeder hematophagous insects expected to recover transmissible parasites from the dermis. In a recent study using C57BL/6 mice, described as mice resistant to L. major, Stenger et al. (21) showed that a small number of parasites may persist in the regional lymph node, the spleen, and in s...