HIV is transmitted by three main routes: sexual contact, significant exposure to infected body fluids or tissues, and from mother to child during pregnancy, delivery, or breastfeeding (known as vertical transmission). There is no risk of acquiring HIV if exposed to feces, nasal secretions, saliva, sputum, sweat, tears, urine, or vomit unless these are contaminated with blood. It is possible to be co-infected by more than one strain of HIV—a condition known as HIV superinfection.

HIV can be transmitted from mother to child during pregnancy, during delivery, or through breast milk, resulting in the baby also contracting HIV. This is the third most common way in which HIV is transmitted globally. In the absence of treatment, the risk of transmission before or during birth is around 20% and in those who also breastfeed 35%. As of 2008, vertical transmission accounted for about 90% of cases of HIV in children. With appropriate treatment the risk of mother-to-child infection can be reduced to about 1%. Preventive treatment involves the mother taking antiretrovirals during pregnancy and delivery, an elective caesarean section, avoiding breastfeeding, and administering antiretroviral drugs to the newborn. Antiretrovirals when taken by either the mother or the infant decrease the risk of transmission in those who do breastfeed. However, many of these measures are not available in the developing world. If blood contaminates food during pre-chewing it may pose a risk of transmission.

If a woman is untreated, two years of breastfeeding results in an HIV/AIDS risk in her baby of about 17%. Treatment decreases this risk to 1 to 2% per year. Due to the increased risk of death without breastfeeding in many areas in the developing world, the World Health Organization recommends either: (1) the mother and baby being treated with antiretroviral medication while breastfeeding being continued (2) the provision of safe formula. Infection with HIV during pregnancy is also associated with miscarriage.

AIDS dysmorphic syndrome, also called HIV embryopathy, is a cluster of facial malformations seen in children with perinatal HIV infection. Its status as a syndrome is disputed by the research community. Common symptoms of perinatal HIV infection include candidiasis, lymphocytic interstitial pneumonitis, hepatosplenomegaly, and lymphadenopathy.

A study conducted on 452 patients revealed that the genotype responsible for higher IL-10 expression makes HIV infected people more susceptible to tuberculosis infection. Another study on HIV-TB co-infected patients also concluded that higher level of IL-10 and IL-22 makes TB patient more susceptible to Immune reconstitution inflammatory syndrome (IRIS). It is also seen that HIV co-infection with tuberculosis also reduces concentration of immunopathogenic matrix metalloproteinase (MMPs) leading to reduced inflammatory immunopathology.

When HIV-negative children take isoniazid after they have been exposed to tuberculosis, their risk to contract tuberculosis is reduced. A Cochrane review investigated whether giving isoniazid to HIV-positive children can help to prevent this vulnerable group from getting tuberculosis. They included three trials conducted in South Africa and Botswana and found that isoniazid given to all children diagnosed with HIV may reduce the risk of active tuberculosis and death in children who are not on antiretroviral treatment. For children taking antiretroviral medication, no clear benefit was detected.

AIDS-related complex, or ARC, was introduced after discovery of the HIV (Human Immunodeficiency Virus) when the medical community became aware of the inherent difficulties associated with treating patients suffering from an advanced case of HIV which gave rise to the term Acquired Immune Deficiency Syndrome (AIDS). The necessity for doctors to quickly and accurately understand the special needs of unknown patients suffering from AIDS in an emergency room situation was addressed with the creation of the term ARC.

ARC is "A prodromal phase of infection with the human immunodeficiency virus (HIV). Laboratory criteria separating AIDS-related complex ( ARC) from AIDS include elevated or hyperactive B-cell humoral immune responses, compared to depressed or normal antibody reactivity in AIDS; follicular or mixed hyperplasia in ARC lymph nodes, leading to lymphocyte degeneration and depletion more typical of AIDS; evolving succession of histopathological lesions such as localization of Kaposi's sarcoma, signaling the transition to the full-blown AIDS."

Clinical use of this term was widely discontinued by the year 2000 in the United States after having been replaced by modern laboratory criteria.

HIV infection rates in central Africa are generally moderate to high.

HIV infection rates in eastern Africa are generally moderate to high.

Little is publicly known about the underlying factors causing the disease. Genetic factors are suspected, but the disease does not appear to be heritable. Also, something in the environment may trigger the disease.

An elevated concentration of autoantibodies that block interferon-gamma was detected in most patients.

With the decrease in the death rate among people with HIV/AIDS receiving new treatments in the 1990s, the rates and severity of epidemic KS also decreased. However, the number of people living with HIV/AIDS is increasing in the United States, and it is possible that the number of people with AIDS-associated Kaposi sarcoma will again rise as these people live longer with HIV infection.

Bats recovering from white-nose syndrome (WNS) may be the first natural occurrence of IRIS, in a report released by the USGS. WNS is typified by a cutaneous infection of the fungus "Pseudogymnoascus destructans" during hibernation, when the immune system is naturally suppressed to conserve energy through the winter. This study suggests that bats undergoing an intense inflammation at the site of infection after a return to euthermia is a form of IRIS.

Cryptococcosis is a very subacute infection with a prolonged subclinical phase lasting weeks to months in persons with HIV/AIDS before the onset of symptomatic meningitis. In Sub-Saharan Africa, the prevalence rates of detectable cryptococcal antigen in peripheral blood is often 4–12% in persons with CD4 counts lower than 100 cells/mcL.

Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the healthcare system by avoiding cryptococcal meningitis. The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL. This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy. Cryptococcosis accounts for 20-25% of the mortality after initiating HIV therapy in Africa. What is effective preemptive treatment is unknown, with the current recommendations on dose and duration based on expert opinion. Screening in the United States is controversial, with official guidelines not recommending screening, despite cost-effectiveness and a 3% U.S. cryptococcal antigen prevalence in CD4<100 cells/μL.

Cryptococcosis is a defining opportunistic infection for AIDS, and is the second-most-common AIDS-defining illness in Africa. Other conditions that pose an increased risk include certain lymphomas (e.g., Hodgkin's lymphoma), sarcoidosis, liver cirrhosis, and patients on long-term corticosteroid therapy.

Distribution is worldwide in soil. The prevalence of cryptococcosis has been increasing over the past 20 years for many reasons, including the increase in incidence of AIDS and the expanded use of immunosuppressive drugs.

In humans, "C. neoformans" causes three types of infections:

- Wound or cutaneous cryptococcosis

- Pulmonary cryptococcosis

- Cryptococcal meningitis.

Cryptococcal meningitis (infection of the meninges, the tissue covering the brain) is believed to result from dissemination of the fungus from either an observed or unappreciated pulmonary infection. Often there is also silent dissemination throughout the brain when meningitis is present. "Cryptococcus gattii" causes infections in immunocompetent people (fully functioning immune system), but "C. neoformans v. grubii", and "v. neoformans" usually only cause clinically evident infections in persons with some form of defect in their immune systems (immunocompromised persons). People with defects in their cell-mediated immunity, for example, people with AIDS, are especially susceptible to disseminated cryptococcosis. Cryptococcosis is often fatal, even if treated. It is estimated that the three-month case-fatality rate is 9% in high-income regions, 55% in low/middle-income regions, and 70% in sub-Saharan Africa. As of 2009 there were globally approximately 958,000 annual cases and 625,000 deaths within three months after infection.

Although the most common presentation of cryptococcosis is of "C. neoformans" infection in an immunocompromised person (such as persons living with AIDS), the "C. gattii" is being increasingly recognised as a pathogen in what is presumed to be immunocompetent hosts, especially in Canada and Australia. This may be due to rare exposure and high pathogenicity, or to unrecognised isolated defects in immunity, specific for this organism.

HIV-SGD is more prevalent in HIV positive children than HIV positive adults, at about 19% and 1% respectively. Unlike other oral manifestations of HIV/AIDS such as Kaposi sarcoma, oral hairy leukoplakia and oral candidiasis, which decreased following the introduction of highly active antiretroviral therapy (HAART), HIV-SGD has increased.

The suppression of CD4 T cells by HIV (or by immunosuppressive drugs) causes a decrease in the body's normal response to certain infections. Not only does this make it more difficult to fight the infection, it may mean that a level of infection that would normally produce symptoms is instead undetected (subclinical infection). If the CD4 count rapidly increases (due to effective treatment of HIV, or removal of other causes of immunosuppression), a sudden increase in the inflammatory response produces nonspecific symptoms such as fever, and in some cases a worsening of damage to the infected tissue.

There are two common IRIS scenarios. The first is the “unmasking” of an opportunistic infection. The second is the “paradoxical” symptomatic relapse of a prior infection despite microbiologic treatment success. Often in paradoxical IRIS, microbiologic cultures are sterile. In either scenario, there is hypothesized reconstitution of antigen-specific T cell-mediated immunity with activation of the immune system following HIV therapy against persisting antigen, whether present as intact organisms, dead organisms, or debris.

Though these symptoms can be dangerous, they also indicate that the body may now have a better chance to defeat the infection. The best treatment for this condition is unknown. In paradoxical IRIS reactions, the events will usually spontaneously get better with time without any additional therapy. In unmasking IRIS, the most common treatment is to administer antibiotic or antiviral drugs against the infectious organism. In some severe cases, anti-inflammatory medications, such as corticosteroids are needed to suppress inflammation until the infection has been eliminated.

Infections most commonly associated with IRIS include "Mycobacterium tuberculosis" and cryptococcal meningitis. Persons living with AIDS are more at risk for IRIS if they are starting for the first time, or if they have recently been treated for an opportunistic infection (OI). It is generally advised that when patients have low initial CD4 T cell count and opportunistic infection at the time of their HIV diagnosis, they receive treatment to control the opportunistic infections before HAART is initiated approximately two weeks later. This is true for most OIs, except for OIs involving the central nervous system.

Primary cerebral lymphoma (or "primary central nervous system lymphoma") is a form of NHL. It is very rare in immunocompetent people, with an incidence of 5–30 cases per million person-years. However the incidence in immunocompromised individuals is greatly increased, up to 100 per million person-years.

Primary cerebral lymphoma is strongly associated with Epstein–Barr virus (EBV). The presence of EBV DNA in cerebrospinal fluid is highly suggestive of primary cerebral lymphoma.

Treatment of AIDS patients with antiretroviral drugs reduces the incidence of primary cerebral lymphoma.

Blood tests to detect antibodies against KSHV have been developed and can be used to determine whether a person is at risk for transmitting infection to their sexual partner, or whether an organ is infected prior to transplantation. However, these tests are not available except as research tools, and, thus, there is little screening for persons at risk for becoming infected with KSHV, such as people following a transplant.

The incidence of Hodgkin's disease in the general population is about 10–30 per million person-years. This increases to 170 per million person-years in HIV positive patients.

Many of these viruses are controlled through laboratory screening tests. These fall into three basic varieties: antibody tests, nucleic acid tests (NAT), and surrogate tests. Antibody tests look for the immune system's response to the infection. Nucleic acid tests look for the genetic material of the virus itself. The third variety are tests that are not specific to the disease but look for other related conditions.

High risk activities for transfusion transmitted infections vary, and the amount of caution used for screening donors varies based on how dangerous the disease is. Most of the viral diseases are spread by either sexual contact or by contact with blood, usually either drug use, accidental needle injuries among health care workers, unsterilized tattoo and body piercing equipment, or through a blood transfusion or transplant. Other vectors exist.

Whether a donor is considered to be at "too high" of a risk for a disease to be allowed to donate is sometimes controversial, especially for sexual contact. High risk sexual activity is defined in many different ways, but usually includes:

- Sex in exchange for money or drugs.

- Men who have sex with men, the most controversial criterion.

- A recent history of sexually transmitted disease.

- Sex with a person who has had a positive test or was at high risk for a disease that can be spread in blood transfusions.

Human immunodeficiency virus salivary gland disease (abbreviated to HIV-SGD, and also termed HIV-associated salivary gland disease), is swelling of the salivary glands and/or xerostomia in individuals infected with human immunodeficiency virus.

The disease PCP is relatively rare in people with normal immune systems, but common among people with weakened immune systems, such as premature or severely malnourished children, the elderly, and especially persons living with HIV/AIDS (in whom it is most commonly observed). PCP can also develop in patients who are taking immunosuppressive medications. It can occur in patients who have undergone solid organ transplantation or bone marrow transplantation and after surgery. Infections with "Pneumocystis" pneumonia are also common in infants with hyper IgM syndrome, an X-linked or autosomal recessive trait.

The causative organism of PCP is distributed worldwide and "Pneumocystis" pneumonia has been described in all continents except Antarctica. Greater than 75% of children are seropositive by the age of 4, which suggests a high background exposure to the organism. A post-mortem study conducted in Chile of 96 persons who died of unrelated causes (suicide, traffic accidents, and so forth) found that 65 (68%) of them had pneumocystis in their lungs, which suggests that asymptomatic pneumocystis infection is extremely common.

"Pneumocystis jirovecii" was originally described as a rare cause of pneumonia in neonates. It is commonly believed to be a commensal organism (dependent upon its human host for survival). The possibility of person-to-person transmission has recently gained credence, with supporting evidence coming from many different genotyping studies of "Pneumocystis jirovecii" isolates from human lung tissue. For example, in one outbreak of 12 cases among transplant patients in Leiden, it was suggested as likely, but not proven, that human-to-human spread may have occurred.

A primary central nervous system lymphoma (PCNSL), also known as microglioma and primary brain lymphoma, is a primary intracranial tumor appearing mostly in patients with severe immunodeficiency (typically patients with AIDS). PCNSLs represent around 20% of all cases of lymphomas in HIV infections (other types are Burkitt's lymphomas and immunoblastic lymphomas). Primary CNS lymphoma is highly associated with Epstein-Barr virus (EBV) infection (> 90%) in immunodeficient patients (such as those with AIDS and those immunosuppressed), and does not have a predilection for any particular age group. Mean CD4+ count at time of diagnosis is ~50/uL. In immunocompromised patients, prognosis is usually poor. In immunocompetent patients (that is, patients who do not have AIDS or some other immunodeficiency), there is rarely an association with EBV infection or other DNA viruses. In the immunocompetent population, PCNSLs typically appear in older patients in their 50's and 60's. Importantly, the incidence of PCNSL in the immunocompetent population has been reported to have increased more than 10-fold from 2.5 cases to 30 cases per 10 million population. The cause for the increase in incidence of this disease in the immunocompetent population is unknown.

The virus that causes AIDS is the best known of the transfusion-transmitted infections because of high-profile cases such as Ryan White, a haemophiliac who was infected through factor VIII, a blood-derived medicine used to treat the disease. Another person who died of medically acquired HIV/AIDS was Damon Courtenay, who died in 1991 due to a bad batch of factor VIII.

The standard test for HIV is an enzyme immunoassay test that reacts with antibodies to the virus. This test has a window period where a person will be infected but not yet have an immune response. Other tests are used to look for donors during this period, specifically the p24 antigen test and nucleic acid testing.

In addition to the general risk criteria for viruses, blood donors are sometimes excluded if they have lived in certain parts of Africa where subtypes of HIV that are not reliably detected on some tests are found, specifically HIV group O. People who have been in prison for extended periods are also excluded for HIV risk.

Patients with AIDS and PCNSL have a median survival of only 4 months with radiotherapy alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent opportunistic infections rather than the lymphoma itself. Extended survival has been seen, however, in a subgroup of AIDS patients with CD4 counts of more than 200 and no concurrent opportunistic infections, who can tolerate aggressive therapy consisting of either methotrexate monotherapy or vincristine, procarbazine, or whole brain radiotherapy. These patients have a median survival of 10–18 months. Of course, highly active antiretroviral therapy (HAART) is critical for prolonged survival in any AIDS patient, so compliance with HAART may play a role in survival in patients with concurrent AIDS and PCNSL.