Nancy J. Alexander

Bio: Nancy J. Alexander is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Sperm & Vasectomy. The author has an hindex of 30, co-authored 79 publications receiving 3066 citations. Previous affiliations of Nancy J. Alexander include Eastern Virginia Medical School & Oregon Health & Science University.

Progesterone implants enhance SIV vaginal transmission and early virus load

Abstract: Simian immunodeficiency virus (SIV) can cross the intact vaginal epithelium to establish a systemic infection in macaques (mac). Using this SIVmac model, we found that subcutaneous progesterone implants, which could mimic hormonally based contraceptives, thinned the vaginal epithelium and enhanced SIV vaginal transmission 7.7-fold over that observed in macaques treated with placebo implants and exposed to SIV in the follicular phase of the menstrual cycle. Progesterone treatment also increased the number of SIV DNA-positive cells in the vaginal lamina propria as detected by in situ polymerase chain reaction analysis. Moreover, plasma viral RNA was elevated for the first three months in macaques with progesterone implants, and three of the progesterone-treated macaques developed relatively rapid disease courses. This study shows that SIV genital infection and disease course are enhanced by subcutaneous implants containing progesterone when compared with the rate of vaginal transmission in the follicular phase.

Monoclonal antibody to a human germ cell membrane glycoprotein that inhibits fertilization.

Abstract: A monoclonal antibody to an antigen in the human germ cell membrane did not agglutinate or immobilize sperm but inhibited binding and penetration of zona-free hamster ova by human sperm and blocked murine fertilization in vitro. The antibody, of the 2a subclass of immunoglobulin G, was germ cell-specific but not species-specific. It recognized a single antigen of 23 kilodaltons that has been isolated from human germ cells. This fertilization antigen, located on the postacrosome , midpiece, and tail of human sperm, is a glycoprotein of testicular origin associated with some types of human involuntary immunoinfertility .

Vasectomy: long-term effects in the rhesus monkey.

Abstract: Biopsies of the ductuli efferentes and of caput mid- and cauda epididymidis were taken from normal rhesus and stumptailed monkeys and from rhesus monkeys vasectomized for 1 month 3 months and 3 5 and 7 years previously. Changes were most prevalent in the ductuli efferentes. In normal animals spermatozoa were less frequently found in the lumen of the ductuli but were packed together and stored in large numbers in the caudal portion of the epididymis. In animals vasectomized for 2 or more years the ductuli were enlarged as much as four times in diameter and the epithelial basal lamina thickened considerably. Spermatozoa became agglutinated in the lumen of the ductuli where they were ingested by macrophages. Fluorescein-labelled antibody and electron microscopy showed the thickened basal lamina to be in the site of antigen-antibody complexing. The author postulated that long-term vasectomy results in an autoimmune response to spermatozoa that may aid in the disposal of the spermatozoa still being produced by the testes but lacking an exit passage. These autoimmune changes after long-term vasectomy may reduce the chance for successful pregnancy after surgical re-anastomosis of the vas deferens.

Vasectomy increases the severity of diet-induced atherosclerosis in Macaca fascicularis.

Abstract: Diet-induced atherosclerosis developed more extensively in vasectomized cynomolgus monkeys (Macaca fascicularis) than in sham-vasectomized control monkeys fed the same diet. The effect was most pronounced in the abdominal aortas, carotid arteries, distal segments of the coronary arteries, and intracranial cerebral arteries. Antibodies to sperm developed in all vasectomized monkeys, and complement and immunoglobulins were associated with atherosclerotic plaques in some of the vasectomized animals. The immunological response to sperm antigens that often accompanies vasectomy may exacerbate atherosclerosis.

Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies.

Abstract: The development of the human immunodeficiency virus-1 (HIV-1)/simian immunodeficiency virus (SIV) chimeric virus macaque model (SHIV) permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, others, and we have shown that passively infused antibody can protect against an intravenous challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. After controlling the macaque estrous cycle with progesterone, anti-HIV-1 neutralizing monoclonal antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all five control monkeys displayed high plasma viremia and rapid CD4 cell decline, 14 antibody-treated macaques were either completely protected against infection or against pathogenic manifestations of SHIV-infection. Infusion of all three antibodies together provided the greatest amount of protection, but a single monoclonal antibody, with modest virus neutralizing activity, was also protective. Compared with our previous intravenous challenge study with the same virus and antibodies, the data indicated that greater protection was achieved after vaginal challenge. This study demonstrates that antibodies can affect transmission and subsequent disease course after vaginal SHIV-challenge; the data begin to define the type of antibody response that could play a role in protection against mucosal transmission of HIV-1.

Sexual transmission of HIV

Abstract: Transmission through sexual contact accounts for 75 to 85 percent of the nearly 28 million infections with the human immunodeficiency virus (HIV) that have occurred so far1 The probability of infection through sexual contact, although it varies greatly, appears to be lower than that of infection through other routes of exposure (Figure 1) The variability observed among and within routes of HIV exposure depends partly on the viral dose and also on whether the virus is transmitted directly into the blood or onto a mucous membrane In addition, these differences are influenced by a variety of host factors, including both

Immune mechanisms in atherosclerosis.

Abstract: Atherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate and effect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstable plaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seen a rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation of immune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there are encouraging data suggesting that immune modulation as well as immunization can reduce the progression of the disease. This review provides an overview of our current understanding of the role of immune mechanisms in atherosclerosis.

Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells.

Abstract: In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.

Fc receptor but not complement binding is important in antibody protection against HIV

Abstract: Many effective vaccines act by inducing neutralizing antibodies, and this approach is a top priority in work on HIV vaccines. But a new study suggests that anti-HIV antibodies are most effective when they act in two ways: through neutralization — killing the virus outright and blocking its entry into T cells — and by killing infected cells. The use of engineered versions of a neutralizing human antibody that protects against HIV in a monkey model shows that protection is dependent not only the antibody's neutralizing activity, but also on its interaction with Fc receptors on effector cells, which may act to reduce virus yield from infected cells. This work suggests that the best results might be achieved with vaccines that recruit both neutralizing antibodies and cell-mediated immunity via agents such as macrophages and cytokinins, rather than antibodies. Passively administered neutralizing antibodies have been shown to protect macaques against challenge by the HIV/SIV chimeric SHIV. The antiviral effects of the monoclonal antibody b12 are crucially dependent on antibody effector mechanisms. Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine1,2. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge3,4. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.