Robert M. Friedman

A Prospective Study of Human Immunodeficiency Virus Type 1 Infection and the Development of AIDS in Subjects with Hemophilia

We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (+/- SE) of 13.3 +/- 5.3 percent for ages 1 to 17, 26.8 +/- 6.4 percent for ages 18 to 34, and 43.7 +/- 16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 years old had a higher incidence of low CD4 counts than younger subjects (P less than or equal to 0.005), whereas adolescents had a low rate of anti-p24 loss (P = 0.0007) and subjects 1 to 17 years old had a lower incidence of AIDS after loss of anti-p24 (P = 0.03). These findings not only demonstrate that the risk of AIDS is related directly to age but also suggest that older adults are disproportionately affected during the earlier phases of HIV disease, that adolescents may have a low replication rate of HIV, and that children and adolescents may tolerate severe immunodeficiency better because they have fewer other infections or because of some unmeasured, age-dependent cofactor or immune alteration in the later phase of HIV disease.

Cholera toxin inhibits interferon action

Abstract Cholera toxin added together with interferon inhibited the establishment of antiviral activity in mouse L-cells. Cholera toxin has no effect on antiviral activity established before its addition; however, treatment of cells with the toxin before addition of interferon also inhibited the establishment of antiviral activity.

An interferon-induced increase in cyclic AMP levels precedes the establishment of the antiviral state.

Abstract Mouse interferon induces an increase in cyclic AMP levels in interferon-sensitive mouse Ly cells but not in interferon-insensitive human KB-3 cells. The interferon-induced elevation in cyclic AMP precedes the induction of antiviral activity. Although interferon stimulation of the adenylate cyclase activity of Ly cell plasma membranes has not been detected, interferon is effective in stimulating this activity in plasma membranes from rat thyroid cells.

Actinomycin D: inhibition of phospholipid synthesis in chick embryo cells.

When chick embryo fibroblasts are exposed to actinomycin D for 30 minutes to 3 hours, there is progressive inhibition of phospholipid synthesis, so that by 3 hours the inhibition is 40 percent. All phospholipids are affected. Since this inhibition is twice as great as the inhibition of protein synthesis, some effects of actinomycin D previously ascribed to decreased protein synthesis must be reevaluated.

Stimulation of interferon production in human lymphocytes by mitogens.

Summary Phytohemagglutinin (PHA), poke weed mitogen, and streptolysin-O, all agents capable of stimulating mitosis in human lymphocytes in vitro also stimulated the production of an antiviral substance with biological, chemical, and physical properties identical to those of human interferon. Upon removal of PHA from human lymphocyte cultures interferon production ceased within 2 hours. Readdition of PHA resulted in reinitiation of interferon production.

Nature and function of the structural phospholipids of an arbovirus.

Abstract Semliki Forest virus, a group A arbovirus, contains a number of structural phospholipids, most of which are hydrolyzed by treatment with purified phospholipase C from Clostridium perfringens . The enzyme treatment does not alter the density at which the virus sediments to equilibrium in sucrose gradients. The infectivity of the virus is preserved despite hydrolysis of more then 60% of its phospholipids by limited enzyme treatment at 37 °C. Longer enzyme treatment at 37 °C results in a marked decrease in infectivity but little additional phospholipid hydrolysis. When phospholipase C treatment was arrested by EDTA after 45% of the phospholipid had been hydrolysed, and the virus was then incubated for an additional 30 minutes at 37 °C, inactivation of the virus also occurred. Inactivation of the virus by the enzyme at 37 °C appeared to be associated with release from the virion of its structural proteins. Thus, the results suggest that phospholipids, while not necessary for viral infectivity, do stabilize the structure of the virus.

Some Factors Affecting the Interferon-Induced Antiviral State

Summary and Conclusions The results of the present study indicate that several factors affect the interferon-induced resistance to viruses in tissue culture. Reaction of cells and interferon results in rapidly increasing antiviral activity over about 7 hours. Thereafter antiviral activity remains relatively stable in the presence of an unchanging amount of interferon in the extracellular fluid. Continued presence of the initial concentration of interferon was required to maintain the established level of resistance. Addition of more interferon resulted in a further rise of resistance. The level of cellular antiviral activity was determined mainly by the concentration of interferon rather than by the amount applied. Maintenance of resistance required continued cellular protein synthesis and also probably required continued cellular RNA synthesis. These findings support the previous proposal that development of antiviral activity by cells exposed to interferon is due to the induction of a cellular antiviral protein. The results also suggest that maintenance of stable antiviral activity in the presence of interferon could be the result of continued induction by interferon of enough antiviral protein to offset decay.

Interferon Induction by Lymphocytic Choriomeningitis Viruses Correlates with Maximum Virulence

Lymphocytic choriomeningitis (LCM) viruses isolated from the blood of persistently infected mice, could be clearly divided into two categories by observing the disease patterns they produced after intracerebral (i.c.) injection in a number of adult inbred and outbred mice. One type (aggressive) caused the classic pattern of convulsive death in 100% of the mice 7 to 9 days after infection, while the other (docile) caused a protracted disease with deaths occurring, if at all, 2 to 4 weeks after infection. Interferon could be detected in the serum of adult mice on the 3rd and 4th day after infection with several independently cloned aggressive, but not docile, viruses. The inability of docile virus to induce interferon was not due to poor or delayed virus replication in the brain. The aggressive pattern of disease could be provoked easily in docile virus-infected mice with the interferon inducers poly(rI) . poly(rC), tilorone hydrochloride or Newcastle disease virus. The amount of interferon produced had little effect on the mean day of death. Mice that differed over 10-fold in their serum interferon levels after LCM infection, either by genetic predisposition or by stimulation with increasing amounts of poly(rI) . poly(rC), presented almost identical patterns of mortality.

A large glycoprotein of moloney leukemia virus derived from interferon-treated cells

Summary Moloney murine leukemia virus produced in interferon-treated mouse thymus and bone marrow cells has a high particle to infectivity ratio (1, 2). This virus contains a prominent glycoprotein with a molecular weight of about 85,000. This large glycoprotein is only a very minor component of Moloney leukemia virus produced in control TB cells and may be an uncleaved precursor to gp 69–71 (3, 4).

Effect of interferon treatment on vesicular stomatitis virus (VSV): Release of unusual particles with low infectivity

Abstract As much as 200-fold inhibition in the titer of infectious vesicular stomatitis virus (VSV) was achieved in cultures of Ly cells treated with 30 reference units/ml of interferon (IF); however, virus particle production, as measured by VSV particle-associated RNA, nucleocapsid (N) protein, or transcriptase, was inhibited a maximum of 10-fold by this concentration of interferon. A significant reduction was seen in the glycoprotein (G) and matrix protein (M) content of VSV from interferon-treated cells. These results indicated that IF-treated cells produce VSV particles with low infectivity. This may be related to the reduced amount of G protein incorporated into such particles. Only 42 S viral RNA was detected in the virus particles produced by interferon-treated cells; these particles did not interfere with the growth of wild-type VSV in BHK or Ly cells. The findings suggested that these particles are not defective-interfering forms of VSV. The results in many respects resemble those previously reported in IF-treated cells infected with murine leukemia viruses.